Alpha2c adrenoreceptor agonists

ABSTRACT

In its many embodiments, the present invention relates to a novel class of phenylmorpholine and phenylthiomorpholine compounds useful as α2C adrenergic receptor agonists, pharmaceutical compositions containing the compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the α2C adrenergic receptor agonists using such compounds or pharmaceutical compositions.

RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 60/711,453, filed on Aug. 25, 2005, herein incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to phenylmorpholine andphenylthiomorpholine compounds useful as α2C adrenergic receptoragonists, pharmaceutical compositions containing the compounds, andmethods of treatment and prevention using the compounds and compositionsto treat disease states such as congestion (including nasal congestion),migraine, congestive heart failure, cardiac ischemia, pain, glaucoma,and psychotic disorders without substantial adverse side effectsassociated with α2A receptor agonist treatments.

BACKGROUND OF THE INVENTION

The initial classification of adrenergic receptors into α- andβ-families was first described by Ahlquist in 1948 (Ahlquist R P, “AStudy of the Adrenergic Receptors,” Am. J. Physiol. 153:586-600 (1948)).Functionally, the α-adrenergic receptors were shown to be associatedwith most of the excitatory functions (vasoconstriction, stimulation ofthe uterus and pupil dilation) and B-adrenergic receptors wereimplicated in vasodilation, bronchodilation and myocardial stimulation(Lands et al., “Differentiation of Receptor Systems Activated bySympathomimetic amines,” Nature 214:597-598 (1967)). Since this earlywork, α-adrenergic receptors have been subdivided into α1- andα2-adrenergic receptors. Cloning and expression of α-adrenergicreceptors have confirmed the presence of multiple subtypes of bothα1-(α1A, α1B, α1D) and α2-(α2A, α2B, α2C) adrenergic receptors (Michelet al., “Classification of α₁-Adrenoceptor Subtypes,”Naunyn-Schmiedeberg's Arch. Pharmacol, 352:1-10 (1995); Macdonald etal., “Gene Targeting—Homing in on α₂-Adrenoceptor-Subtype Function,”TIPS, 18:211-219 (1997)).

Current therapeutic uses of α2 adrenergic receptor drugs involve theability of those drugs to mediate many of the physiological actions ofthe endogenous catecholamines. There are many drugs that act on thesereceptors to control hypertension, intraocular pressure, eye reddeningand nasal congestion and induce analgesia and anesthesia.

α2 adrenergic receptors can be found in the rostral ventrolateralmedulla, and are known to respond to the neurotransmitter norepinephrineand the antihypertensive drug clonidine to decrease sympathetic outflowand reduce arterial blood pressure (Bousquet et al., “Role of theVentral Surface of the Brain Stem in the Hypothesive Action ofClonidine,” Eur. J. Pharmacol., 34:151-156 (1975); Bousquet et al.,“Imidazoline Receptors: From Basic Concepts to Recent Developments,”26:S1-S6 (1995)). Clonidine and other imidazolines also bind toimidazoline receptors (formerly called imidazoline-guanidinium receptivesites or IGRS) (Bousquet et al., “Imidazoline Receptors: From BasicConcepts to Recent Developments,” 26:S1-S6 (1995)). Some researchershave speculated that the central and peripheral effects of imidazolinesas hypotensive agents may be related to imidazoline receptors (Bousquetet al., “Imidazoline Receptors: From Basic Concepts to RecentDevelopments,” 26:S1-S6 (1995); Reis et al., “The Imidazoline Receptor:Pharmacology, Functions, Ligands, and Relevance to Biology andMedicine,” Ann. N.Y. Acad. Sci., 763:1-703 (1995).

Compounds which have adrenergic activity are well known in the art, andare described in numerous patents and scientific publications. The twomain families of adrenergic receptor are termed alpha adrenergicreceptors and beta adrenergic receptors in the art, and each of thesetwo families is known to have subtypes, which are designated by lettersof the alphabet, such as α2A, α2B, and α2C. It is generally known thatadrenergic activity is useful for treating animals of the mammalianspecies, including humans, for curing or alleviating the symptoms andconditions of numerous diseases and conditions. In other words, it isgenerally accepted in the art that pharmaceutical compositions having anadrenergic compound or compounds as the active ingredient are useful fortreating, among other things, glaucoma, chronic pain, migraines, heartfailure, and psychotic disorders. It is also known that compounds havingadrenergic activity, such as α2A agonists, may be associated withundesirable side effects. Examples of such side effects includehyper-and hypotension, sedation, locomotor activity, and bodytemperature variations.

It has been discovered in accordance with the present invention thatadrenergic compounds that act selectively, and preferably evenspecifically, as agonists of the α2C or the α2B/α2C (hereinafterreferred to as α2C or α2B/2C) receptor subtypes in preference over theα2A receptor subtype, with adrenergic compounds that are functionallyselective agonists of the α2C receptor subtype in preference over theα2A receptor subtype and α2B/2C receptor subtype, possess desirabletherapeutic properties associated with adrenergic receptors but withouthaving one or more undesirable side effects such as changes in bloodpressure (e.g., a hypertensive or hypotensive effect) or sedation. Forthe purposes of this present invention, a compound is defined to be anactive agonist of the α2C receptor subtype if the compound's efficacy atthe α2C receptor is ≧30% E_(max) (GTPγS assay). A compound is afunctionally selective agonist of the α2C receptor subtype over the α2Areceptor subtype if the compound's efficacy at the α2C receptor is ≧30%E_(max) (GTPγS assay) and its efficacy at the α2A receptor is ≧30%E_(max) (GTPγS assay).

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with α2C adrenergicreceptors. Furthermore, there is a need to develop compounds that arefunctionally selective for the α2C receptor subtype with respect to theα2A receptor subtype or the α2B/α2C receptor subtype. It is, therefore,an object of this invention to provide compounds useful in the treatmentor prevention or amelioration of such diseases and disorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofheterocyclic compounds as active or functionally selective α2Cadrenergic receptor agonists or metabolites, stereoisomers (e.g.,enantiomers or diasteromers) salts, solvates or polymorphs thereof,methods of preparing such compounds, pharmaceutical compositionscomprising one or more such compounds, methods of preparingpharmaceutical formulations comprising one or more such compounds, andmethods of treatment, prevention, inhibition or amelioration of one ormore conditions associated with α2C receptors using such compounds orpharmaceutical compositions.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts or metabolites, solvates or polymorphsof said compound, said compound having the general structure shown inFormula I:

or a pharmaceutically acceptable salt or metabolite, solvate orpolymorph of said compound, wherein:

A is a 5-membered heterocyclic ring containing 1-3 heteroatoms, and issubstituted with at least one R⁵;

X is —O—, —S(O)_(p)—, or —N(R⁶)—;

J¹, J², J³, and J⁴ are independently —N—, —N(O)— or —C(R²)—, providedthat 0-3 of J¹, J², J³ and J⁴ are —N—;

R² is independently selected from the group consisting of H, —OH, halo,—CN, —NO₂, —(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR⁷′, —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R⁷′, —P(═O)(OR⁷)(OR⁷′), —P(═O)(NR⁷R⁷′)₂, —P(═O)R⁸ ₂, andalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, and heterocyclyl groups optionallysubstituted with at least one R⁵;

Y is selected from the group consisting of a bond, —C(═O)—, —C(═O)NR⁷—,—C(═O)O—, —C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—,—S(O)_(p)—, —SO₂NR⁷—, and —C(S)NR⁷—;

R³ is independently selected from the group consisting of H and (═O),and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵, provided that when n is 3 or 4, no more than 2 of theR³ groups may be (═O);

R⁴ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵;

R⁵ is independently selected from the group consisting of H, halo, —OH,—CN, —NO₂, —NR⁷R⁷′, —SR⁷, and alkyl, alkoxy, alkenyl, alkenyloxy,alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one of halo, —OH, —CN,—NO₂, —NR⁷R⁷′, and —S(O)_(p)R⁷ substituents;

R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R⁷′, and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R⁷′, —SO₂R⁷ and —SO₂NR⁷R⁷′;

R⁷ is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;

R⁷′ is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; or

-   -   R⁷ and R⁷′ together with the nitrogen atom to which they are        attached form a 3- to 8-membered heterocyclyl, heterocyclenyl or        heteroaryl ring having, in addition to the N atom, 1 or 2        additional hetero atoms selected from the group consisting of O,        N, —N(R⁹)— and S, wherein said rings are optionally substituted        by 1 to 5 independently selected R⁵ moieties,

R⁸ is independently selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;

R⁹ is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and

R¹⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups,each of which is optionally substituted with at least one of halo, —OH,—CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;

R¹¹ is a moiety independently selected from the group consisting of Hand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl;

m is 1-5;

n is 1-3;

p is 0-2;

q is 0-6; and

w is 0-4.

The compounds of Formula I can be useful as α2C adrenergic receptoragonists, and can be useful in the treatment and prevention of allergicrhinitis, all types of congestion (including, but not limited to nasalcongestion), migraine, congestive heart failure, cardiac ischemia,glaucoma, and psychotic disorders. Further, the compounds of Formula Ican be useful in the treatment of pain (both chronic and acute), such aspain that is caused by inflammation, neuropathy, arthritis (includingrheumatoid arthritis, diabetes (e.g., diabetes mellitus or diabetesinsipidus) or pain of an unknown origin. Other pain that can be treatedis nociceptive pain and pain that is visceral in origin or pain that issecondary to inflammation or nerve damage in other diseases. Otherutilities for the inventive compounds could include stress-inducedurinary incontinence and neuronal damage from ischemia.

Alternatively, the present invention provides for a method for thetreatment of congestion in a mammal in need thereof which comprisesadministering to a mammal an effective dose of at least one compoundhaving adrenergic activity wherein said compound is a functionallyselective agonist of the α2c receptor.

A further embodiment of the present invention is a method for thetreatment of congestion in a mammal in need thereof which comprisesadministering to a mammal an effective dose of at least one compoundhaving adrenergic activity wherein said compound is a selective agonistof the α2c adrenergic receptor, wherein the functional selective agonistof the α2c receptor has an efficacy that is greated than or equal to 30%E_(max) when assayed in the GTPγS assay .

Another embodiment of the present invention is a method for thetreatment of congestion in a mammal in need thereof without modifyingthe systemic blood pressure at therapeutic doses which comprisesadministering to the mammal an effective dose of at least one compoundhaving adrenergic activity wherein said compound is a functionallyselective agonist of the α2c receptor.

DETAILED DESCRIPTION

In an embodiment, the present invention discloses certain heterocycliccompounds which are represented by structural Formula I, or apharmaceutically acceptable salt or solvate thereof, wherein the variousmoieties are as described above.

In another embodiment, if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ isH, A is 1H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not—C(═O)-naphthyl.

In another embodiment, if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ isH, A is 1H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not—S(O₂)-naphthyl.

In another embodiment, if J¹, J², and J⁴ are each —C(H)—, J³ is —C(Br)—,n is 2, m is 1, R³ is 3-benzyl, R⁴ is H, A is 1 H-imidazol-4-yl, and Xis —N(R⁶)—, then R⁶ is not —C(O₂)benzyl.

In another embodiment, J¹-J⁴ are each —C(R²)—, n is 1, A is imidazolyl,and X is —O—.

In another embodiment, J¹-J⁴ are each —C(H)—, n is 1, A is imidazolyl,and X is —O—.

In another embodiment, J¹-J⁴ are each —C(R²)—, n is 1, A is imidazolyl,and X is —N(R⁶)—.

In another embodiment, J¹-J⁴ are each —C(R²)—, n is 1, A is imidazolyl,and X is —S(O)_(p)—.

In another embodiment, R² is independently selected from H, —OH, halo,—CN, —NO₂, —(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR⁷′, —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R⁷′, —P(═O)(OR⁷)(OR⁷′), —P(═O)(NR⁷R⁷′)₂, —P(═O)R⁸ ₂,alkyl, alkoxy and polyhaloalkoxy.

In another embodiment, R³ is independently selected from H, alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵.

In another embodiment, R³ is independently selected from H, alkyl andhaloalkyl.

In another embodiment, R⁴ is independently selected from H, alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵.

In another embodiment, R⁴ is independently selected from H, alkyl,allyl, and haloalkyl.

In another embodiment, R⁵ is independently selected from H, halo,—NR⁷R⁷′, —SR⁷, alkyl, and alkoxy.

In another embodiment, R⁶ is independently selected from H, alkyl,haloalkyl, cycloalkyl, —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R⁷′, —SO₂R⁷ and—SO₂NR⁷R⁷′.

In another embodiment, R⁷ is independently chosen from H, alkyl,haloalkyl, cycloalkyl, aryl, and heteroaryl.

In another embodiment, R⁷′ is independently chosen from H, alkyl,haloalkyl, cycloalkyl, aryl, and heteroaryl.

In another embodiment, R⁷ and R⁷′ together with the N atom to which theyare attached form a aziridine, azetidine, pyrrole, pyrrolidine,piperidine, piperazine or morpholine ring, each of which are optionallysubstituted by R⁵.

In another embodiment, R⁸ is independently chosen from alkyl, haloalkyl,cycloalkyl, aryl, and heteroaryl.

In another embodiment, m is 1 or 2.

In another embodiment, n is 1 or 2.

In another embodiment, n is 1.

In another embodiment, q is 0, 1, 2, or 3.

In another embodiment, the present invention discloses compounds whichare represented by structural formulae II-V or a pharmaceuticallyacceptable salt, solvate or ester thereof, wherein the various moietiesare as described above:

wherein z is 0-3 and R¹ is selected from the group consisting of H, —OH,halo, —CN, —NO₂, —SR⁷, —(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR⁷′, —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═C NR⁷R⁷′, —P(═O)(OR⁷)(OR⁷′), —P(═O)(NR⁷R⁷′)₂, —P(═O)R⁸ ₂and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵.

An inventive group of compounds is shown in below:

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Congestion” refers to all type of congestion including, but not limitedto, congestion associated with perennial allergic rhinitis, seasonalallergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitismedicamentosa, sinusitis, acute rhinosinusitis, or chronicrhinosinusitis or when the congestion is caused by polyps or is virallyinduced, such as congestion associated with the common cold.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Halogen” and “Halo” mean fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine or bromine, and more preferred arefluorine and chlorine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y₁Y₂N-alkyl-,

Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or differentand are independently selected from the group consisting of hydrogen,alkyl, aryl, and aralkyl.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protected moieties are also consideredpart of this invention. The heterocyclyl can be optionally substitutedby one or more “ring system substituents” which may be the same ordifferent, and are as defined herein. The nitrogen or sulfur atom of theheterocyclyl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

It should be noted that in heterocyclyl ring systems of this invention,there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, aswell as there are no N or S groups on carbon adjacent to anotherheteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl. “Heterocyclylalkyl” means aheterocyclyl-alkyl group in which the heterocyclyl and the alkyl are aspreviously described. Preferred heterocyclylalkyls contain a lower alkylgroup, Non-limiting examples of suitable heterocyclylalkyl groupsinclude piperidylmethyl, piperidylethyl, pyrrolidylmethyl,morpholinylpropyl, piperazinylethyl, azindylmethyl, azetidylethyl,oxiranyipropyl and the like. The bond to the parent moiety is throughthe alkyl group.

“Heterocyclenyl” (or “heterocycloalkeneyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined above. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable monocyclic azaheterocyclenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limitingexamples of suitable oxaheterocyclenyl groups include3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and thelike. Non-limiting example of a suitable multicyclic oxaheterocyclenylgroup is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an organic acid group in which the —OH of the carboxylgroup is replaced by some other substituent. Suitable non-limitingexamples include H—C(O)—, alkyl-C(O)—, cycloalkyl-C(O)—,heterocyclyl-C(O)—, and heteroaryl-C(O)— groups in which the variousgroups are as previously described. The bond to the parent moiety isthrough the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound' or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

It is noted that carbons of formula I can be replaced with 1-3 siliconatoms, provided all valency requirements are satisfied.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, N.Y.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or formula, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula I incorporates a —NH— functional group, such asa in a primary or secondary amine or in a nitrogen-containingheterocycle, such as imidazole or piperazine ring, a prodrug can beformed by the replacement of a hydrogen atom in the amine group with agroup such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl whereR and R′ are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl,benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylaminomorpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in producing the desired therapeutic, ameliorative, inhibitoryor preventative effect.

“Capsule” is meant to describe a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

“Tablet” is meant to describe a compressed or molded solid dosage formcontaining the active ingredients with suitable diluents. The tablet canbe prepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation or by compaction.

“Oral gels” is meant to describe to the active ingredients dispersed orsolubilized in a hydrophillic semi-solid matrix.

“Powders for constitution” refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

“Diluent” refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

“Disintegrants” refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

“Binders” refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

“Lubricant” is meant to describe a substance added to the dosage form toenable the tablet, granules, etc. after it has been compressed, torelease from the mold or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate or potassium stearate; stearic acid; high melting pointwaxes; and water soluble lubricants such as sodium chloride, sodiumbenzoate, sodium acetate, sodium oleate, polyethylene glycols andd'l-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present on the surfaces of the granulesand in between them and the parts of the tablet press. The amount oflubricant in the composition can range from about 0.2 to about 5% byweight of the composition, preferably from about 0.5 to about 2%, morepreferably from about 0.3 to about 1.5% by weight.

“Glidents” means materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

“Coloring agents” refers to excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

“Bioavailability” refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control. Conventional methods for preparing tablets are known. Suchmethods include dry methods such as direct compression and compressionof granulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula III contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of Formula I, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons or sulfurs on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate” “prodrug” and the like, is intendedto equally apply to the salt, solvate and prodrug of enantiomers,stereoisomers, rotamers, tautomers, racemates or prodrugs of theinventive compounds.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

Polymorphic forms of the compounds of formula I, and of the salts,solvates and prodrugs of the compounds of formula I, are intended to beincluded in the present invention

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H , ¹¹O and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be useful asα2C adrenoreceptor agonists.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula I. An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula I, or apharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more therapeuticagents such as, for example, steroids, PDE-4 inhibitors, anti-muscarinicagents, cromolyn sodium, H₁ receptor antagonists, 5-HT₁ agonists,NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin IIreceptor agonists, β-blockers, β-agonists (including both short and longacting), leukotriene antagonists, diuretics, aldosterone antagonists,ionotropic agents, natriuretic peptides, pain management/analgesicagents, anti-anxiety agents, anti-migraine agents, and therapeuticagents suitable for treating heart conditions, psychotic disorders, andglaucoma.

Suitable steroids include prednisolone, fluticasone (including allesters such as the propionate or furoate esters), triamcinolone,beclomethasone, mometasone (including any ester form such as mometasonefuroate), budasamine, ciclesonide, betamethasone, dexamethasone,prednisone, flunisolide, and cortisone.

Suitable PDE-4 inhibitors include roflumilast, theophylline, rolipram,piclamilast, cilomilast, and CDP-840.

Suitable antiimuscarinic agents include ipratropium bromide andtiatropium bromide.

Suitable H₁ antagonists include astemizole, azatadine, azelastine,acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratidine, diphenhydramine, doxylamine, dimethindene,ebastine, epinastine, efletirizeine, fexofenadine, hydroxyzine,ketotifen, loratidine, levocabastine, meclizine, fexofenadine,hydroxyzine, ketotifen, loratadine, levocabastine, meclizine,mizolastine, mequitazine, mianserin, noberastine, norastemizole,picumast, pyrilamine, promethazine, terfenadine, tripelennamine,temelastine, trimeprazine or triprolidine.

Suitable anti-inflammatory agents include aspirin, diclofenac,diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, andtolmetin.

Suitable aldosterone antagonists include spironolactone.

Suitable ionotropic agents include digitalis.

Suitable angiotensin II receptor agonists include irbesartan andlosartan.

Suitable diuretics include spironolactone, methyclothiazide, bumetanide,torsemide, hydroflumethiazide, trichlormethiazide, hydroclorothiazide,triamterene, ethacrynic acid, methyclothiazide, hydrochlorothiazide,benzthiazide, hydrochlorothiazide, quinethazone, hydrochlorothiazide,chlorthalidone, furosemide, indapamide, hydroclorothiazide, triamterene,trichlormethiazide, hydrochlorothiazide, amiloride HCl, amiloride HCl,metolazone, trichlormethiazide, bendroflumethiazide,hydrochlorothiazide, polythiazide, hydroflumethiazide, chlorthalidone,and metolazone.

Suitable pain management/analgesic agents include Celecoxib,amitriptyline, ibuprofen, naproxen, gabapentin, tramadol, rofecoxib,oxycodone HCl, acetaminophenoxycodone HCl, carbamazepine, diclofenac,diclofenac, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac tromethamine, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac,tolmetin sodium, valdecoxib, diclofenac/misoprostol, oxycontin, vicodin,darvocet, morphine sulfate, dilaudid, stadol, stadol NS, acetaminophenwith codeine, acetaminophen with codeine #4, Lidoderm® patches, andpercocet.

Suitable β-blockers include acebutolol, atenolol,atenolol/chlorthalidone, betaxolol, bisoprolol fumarate,bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol,propranolol, propranolol/HCTZ, sotalol, and timolol.

Suitable β-agonists include dobutamine, ritodrine, salbutamol,levalbuterol, metaproternol, formoterol, fenoterol, bambuterol,brocaterol, clenbuterol, terbutaline, tulobuterol, epinephrine,isoprenalin, and hexoprenalin.

Suitable leukotriene antagonists include levamisole.

Suitable anti-migraine agents include rovatriptan succinate, naratriptanHCl, rizatriptan benzoate, sumatriptan succinate, zolmitriptan,almotriptan malate, methysergide maleate, dihydroergotamine mesylate,ergotamine tartrate, ergotamine tartrate/caffeine, Fioricet®,Fiorninal®, Depakene®, and Depakote®.

Suitable anti-anxiety and anti-depressant agents include amitriptylineHCl, bupropion HCl, citalopram hydrobromide, clomipramine HCl,desipramine, fluoxetine, fluvoxamine maleate, maprotiline HCl,mirtazapine, nefazodone HCl, nortriptyline, paroxetine HCl,protriptyline HCl, sertraline HCl, doxepin, and trimipramine maleate.

Suitable angiotensin converting enzyme inhibitors include Captopril,enalapril, enalapril/HCTZ, lisinopril, lisinopril/HCTZ, and Aceon®.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I, or a pharmaceuticallyacceptable salt or solvate of said compound and at least onepharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable saltor solvate of said compound and an amount of at least one therapeuticagent listed above, wherein the amounts of the two or more ingredientsresult in desired therapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz), VarianMercury VX-400 (400 MHz), or Bruker-Biospin AV-500 (500 MHz), and arereported as ppm with number of protons and multiplicities indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and C18 column,10-95% CH₃CN—H₂O (with 0.05% TFA) gradient. The observed parent ion isgiven.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; Ph=phenyl, and Ac=acetyl-   μl=microliters-   AcOEt or EtOAc=ethyl acetate-   AcOH or HOAc=acetic acid-   ACN=acetonitrile-   atm=atmosphere-   Boc or BOC=tert-butoxycarbonyl-   DOE=dichloroethane-   DCM or CH₂Cl₂: dichloromethane:-   DIPEA=diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   DMF=dimethylformamide-   DMS=dimethylsulfide-   DMSO=dimethyl sulfoxide-   EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Fmoc=9-fluorenylmethoxycarbonyl-   g=grams-   h=hour-   hal=halogen-   HOBt=1-hydroxybenzotriazole-   LAH=lithium aluminum hydride-   LCMS=liquid chromatography mass spectrometry-   min=minute-   mg=milligrams-   mL=milliliters-   mmol=millimoles-   MCPBA=3-chloroperoxybenzoic acid-   MeOH=methanol-   MS=mass spectrometry-   NMR=nuclear magnetic resonance spectroscopy-   RT or rt=room temperature (ambient, about 25° C.)-   TEA or Et₃N=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TMS=trimethylsilyl-   Tr=triphenylmethyl

Examples

The compounds of this invention can be prepared as generally describedin Schemes 1 and 2, and the following examples. Scheme 1 shows anapproach in which S1 and S2 are joined together. Examples of theseapproaches include reaction of SI with an electrophilic S2 compound,where R′ is a carboxaldehyde (coupling by reductive amination),carboxylic acid (amide coupling) or halide (coupling by alkylation).

Scheme 2 discloses a general approach for synthesizing S1, whereby anappropriately substituted aniline S4 can be converted to S1 through asingle or multistep ring cyclization approach.

Compounds of formula S3 can be prepared by the general methods outlinedabove. Specifically exemplified compounds were prepared from S4 or S1fragments as described in the examples below or from starting materialsknown in the art.

The starting materials and reagents used in preparing compoundsdescribed are either available from commercial suppliers such as AldrichChemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA)or were prepared by literature methods known to those skilled in theart. These examples are being provided to further illustrate the presentinvention. They are for illustrative purposes only; the scope of theinvention is not to be considered limited in any way thereby.

Preparative Example 1

A solution of 3,4-dihydro-2H-1,4-benzoxazine 1A (0.1 g, 0.75 mmol) inDCE (10 mL) was treated with imidazole-4-carboxaldehye 1B (0.11 g, 1.1mmol), NaBH(OAc)₃ (0.47 g, 2.2 mmol), and AcOH (one drop) and stirred at60° C. overnight. The reaction was then diluted with CH₂Cl₂, washed withsaturated aqueous NaHCO₃, dried over Na₂SO₄, and concentrated.Chromatography (0-4% 7 N NH₃—MeOH/CH₂Cl₂) provided 1 as a beige solid(0.08 g, 50%). LMCS m/z 216 (MH+).

Alternatively, the title compound 1 can be synthesized by the reactionof 1A and resin bound imidazole-4-carboxaldehye 1D as described below:

Novabiochem Resin 1C (100-200 mesh, 1% DVB, 1.4 mmol/g, 5 g) wassuspended in anhydrous DMF (25 mL) and DCE (25 mL) and treatedsequentially with 1B (2 g, 21 mmol) and TEA (2.96 mL, 21 mmol). Theresin was shaken overnight and washed with DMF (3×), MeOH (3×), and DCM(4×) then dried in vacuo overnight. The resulting resin 1D (100 mg, 1.4mmol/g, 0.14 mmol) was suspended in DCE (4 mL) and treated with 1A (94.5mg, 0.7 mmol) and NaBH(OAc)₃ (148 mg, 0.7 mmol). The reaction was shakenovernight and washed with DMF (3×), MeOH (3×), and DCM (4×), then driedin vacuo. The resulting resin was subjected to 30% TFA/DCM, stirred atRT for 2 h and the mixture was concentrated under vacuum. The residuewas purified by Gilson prep-HPLC to afford compound 1 (12.3 mg).

Preparative Example 2

A solution of 3,4-dihydro-2H-1,4-benzoxazine (0.52 g, 3.8 mmol) andthiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1 CH₂Cl₂:DMF (20 mL) wastreated with DIPEA (2.6 ml, 15 mmol), HOBt (1.29 g, 9.5 mmol), and EDCl(1.83 g, 9.5 mmol) and stirred at 70° C. overnight. The reaction wasthen diluted with CH₂Cl₂, washed with saturated aqueous NaHCO₃, driedover Na₂SO₄, and concentrated. Chromatography (0-10% 1 N NH₃-MeOH/EtOAc)provided 2A as a red solid (0.54 g, 55%)

Step 2

A solution of 2A (0.094 g, 0.36 mmol) in THF (10 mL) was treated withBH₃—SMe₂ (2M/THF, 0.27 mL, 0.54 mmol) and stirred at reflux for 2 h. Thereaction was concentrated and subjected to chromatography (EtOAc) toprovide 2 as a white solid (0.040 g, 45%). LMCS m/z 246 (MH+).

Preparative Example 3

A mixture of 2-amino-4-nitrophenol (3A, 25.03 g, 0.16 mol) in4-methyl-2-pentanone and water (420 mL, 1:1) was treated with sodiumbicarbonate (32.74 g, 0.39 mol), cooled to 0° C., and treated then withchloroacetyl chloride (15.52 mL, 0.19 mol). The reaction mixture washeated to reflux overnight. After cooling to RT, the mixture wasconcentrated under vacuum. The residue was diluted with water (200 mL)and EtOAc (100 mL), and filtered to give the pale gray solid 3B (26.05g). The filtrate was separated and the aqueous was extracted with EtOAc(3×100 mL). The combined organic layers were washed with water, anddried (MgSO₄), filtered, and concentrated under vacuum to giveadditional light gray solid 3B (7.7 g). The resulting solid(quantitative yield) was used for next reaction without furtherpurification.

To compound 3B (6.76 g, 34.84 mmol) in anhydrous THF (200 mL) was addedBH₃-SMe₂ (2.0M/THF, 35 mL, 69.68 mmol). The mixture was heated to refluxfor 2 h. After cooling to RT, the mixture was quenched with MeOH (10 ml)and heated to reflux for another 10 minutes. The reaction mixture wasconcentrated under vacuum. Chromatography (10%-30% EtOAc/hexanes)provided 3C (6.1 g, 97% for two steps).

A mixture of 3C (4.35 g, 21.16 mmol) in anhydrous dichloroethane (60 mL)was treated with imidazole-4-carboxaldehye (1B, 2.79 g, 28.99 mmol) andAcOH (0.35 mL, 6 mmol). The mixture was stirred at RT for 10 min andthen treated with NaBH(OAc)₃ (15.36 g, 72.48 mmol). The reaction mixturewas stirred at RT overnight, and quenched with 2N NaOH solution,concentrated under vacuum. The residue was diluted with water (50 mL)and extracted with EtOAc (4×100 mL). The organic layer was dried(MgSO₄), filtered, and concentrated under vacuum. Chromatography (DCMcontaining 1 to 5% of 7N NH₃ in MeOH) provided 3D (5.56 g, 89%). MS m/z261 (MH+).

Compound 3D (5.56 g, 21.38 mmol) was dissolved in MeOH/EtOAc (300 mL,1:1), 10% Pd/C (1.11 g, 20% by weight) was carefully added. The mixturewas stirred at RT under a hydrogen balloon overnight and filtered. Thesolvent was evaporated off under vacuum to give a white solid 3E (5.46g, 100%). MS m/z 231 (MH+).

A mixture of amine 3E (2.14 g, 9.30 mmol) in anhydrous DCM (40 mL) wassequentially treated with TEA (3.24 mL, 23.3 mmol) and ClCO₂Me (1.43 mL,18.6 mmol). The mixture was stirred at RT for 2 h, and then quenchedwith 2N NaOH solution. The resulting mixture was stirred for another 2 hand separated. The aqueous layer was extracted with DCM (3×50 mL). Thecombined organic layers were dried (MgSO₄), filtered, and concentratedunder vacuum. Chromatography (DCM containing 1 to 4% of 7N NH₃/MeOH)provided 3 as a white solid (1.64 g, 61%). MS m/z 289 (MH+).

Preparative Example 4

In a manner similar to Example 3, Step 5, amine 3E was treated with TEAand AcCl to provide the compound 4. MS m/z 273 (MH+).

Preparative Example 5

A solution of 3C (3 g, 16.7 mmol) in anhydrous DCM (100 mL) was treatedwith Boc₂O (7.27 g, 33.3 mmol), pyridine (5.39 mL, 66.7 mmol), andcatalytic DMAP. The mixture was stirred at RT overnight and concentratedunder vacuum. The residue was diluted with water (50 mL) and extractedwith EtOAc (3×100 mL). The combined organic layers were dried (MgSO₄),concentrated and subjected to chromatography (5-5% EtOAc/hexanes, yield:3 g, 64%).

The resulting product was hydrogenated in a manner similar to that foundin Example 3, Step 4 to provide 5A.

To amine 5A (1.1 g, 4.4 mmol) in anhydrous THF (15 mL) was added MeNCO(215 mg, 4.4 mmol). The mixture was stirred at RT overnight and thenconcentrated. Chromatography (DCM containing 1 to 5% of 7N NH₃/MeOH)provided 5B (890 mg, 66%).

Compound 5B (890 mg, 2.9 mmol) was stirred at RT in 30% TFA/DCM (14 mL)containing three drops of Et₃SiH for 1 h, and then quenched with 2N NaOHsolution. The mixture was extracted with EtOAc (3×50 mL). The organiclayer was dried (MgSO₄), filtered and concentrated under vacuum. Theresidue (5C, 600 mg) was used in the next reaction without furtherpurification.

In a manner similar to that described in Example 3 (Step 3), compound 5Cwas treated with imidazole-4-carboxaldehyde (1B) to provide titlecompound 5 (56% for two steps). MS m/z 288 (MH+).

Compounds 5D-5F in Table 1 below can be prepared from compound 5A usingvarious capping reagents as shown, followed by Boc-deprotection andreductive alkylation as described above.

TABLE 1

Cpd Reagent R MS (MH+) 5D Methanesulfonic anhydride/pyridine

309 5E

and pyridine

338 5F

and pyridine

302

Preparative Example 6

To a flask with Ac₂O (2.02 mL, 21.4 mmol) at 0° C. was added HCO₂H (0.82mL, 21.4 mmol) by syringe. After stirring at 0° C. for 5 min, themixture was heated up to 55° C. for 2 h, and then was cooled to 0° C.again. Amine 5A (2 g, 8.0 mmol) in anhydrous THF (100 mL) was added andthe mixture was stirred at 0° C. for 30 min. The reaction mixture wasconcentrated under vacuum and diluted with 2 N NaOH solution to pH 9,extracted with EtOAc (3×50 mL). The organic layer was dried (MgSO₄),filtered, and concentrated under vacuum to give a foam 6A (quantitativeyield).

Alternatively, a mixture of compound 5A (17.5 g, 69.9 mmol) in butylformate (700 ml) was heated at 50° C. for 3 h and then left at RTovernight. The reaction mixture was then concentrated, added to 100 mlof 0.5N NaOH, extracted with CH₂Cl₂ (4×), dried with Na₂SO₄, andconcentrated. Chromatography (10%-50% EtOAc/hexane) gave 6A (9.19 g,47%) as a light brown sticky foam.

A mixture of compound 6A (2.75 g, 9.88 mmol) in THF (30 ml) was treatedslowly with BH₃-DMS (2.0 M/THF, 7.8 ml) and then heated at reflux for 3h. The reaction mixture was concentrated, treated with K₂CO₃ (1.5 g) andEtOH, and then stirred overnight at RT. The reaction mixture wasfiltered, concentrated, added to H₂O and extracted with CH₂Cl₂ (4×). Thecombined organic layers were dried with Na₂SO₄, filtered andconcentrated to provide 6B as a clear oil (2.76 g).

A solution of 6B (2.76 g, crude) in CH₂Cl₂ (20 ml) was treated slowlywith MeNCO (1.0 g, 12.5 mmol) and stirred at RT overnight. The reactionmixture was concentrated and chromatographed (50% to 80% EtOAc/hex, 3.10g, 98% yield from 6A). This product (3.10 g, 9.65 mmol) was taken up inof CH₂Cl₂ (80 ml) and deprotected with of TFA (11.5 ml) as described inExample 5, Step 4 (95% yield). A mixture of the resulting amine andaldehyde 1B (1 eq) in a minimal amount of CH₂Cl₂ was treated withTi(OiPr)₄ (1.3 eq). After stirring for 2 h at RT, NaBH₄ (1.2 eq) andEtOH were added. The reaction mixture was then stirred overnight,concentrated, treated with H₂O and extracted with CH₂Cl₂ (4×). Thecombined organic layers were dried with Na₂SO₄, filtered, concentratedand chromatographed (silica gel, 5% MeOH/CH₂Cl₂ w/NH₃) to provide thetitle compound 6 (74% yield). MS m/z 302 (MH+).

Compounds in Table 2 below can be prepared from compound 6B using thevarious capping reagents as shown, followed by Boc-deprotection andreductive alkylation as shown in Example 5.

TABLE 2

Cpd Reagent R MS (MH+) 6C TMSNCO

288 6D

/pyridine

352 6E MeCOCl/ pyridine

303

Compound 6F was prepared as follows: 6A was treated with TFA, followedby reductive alkylation with imidazole-4-carboxaldehyde (1B) asdescribed previously in Example 5 (Step 4) and Example 3 (Step 3). MSm/z 259 (MH+).

In a manner similar to Example 3, Step 2, compound 6F was reduced withBH₃—SMe₂ to provide 6G. MS m/z 245 (MH+).

Preparative Example 7

To a suspension of compound 3D (4.8 g, 18.46 mmol) in anhydrous DCM (200mL) was sequentially added TrCl (5.15 g, 18.46 mmol) and TEA (7.7 mL,55.37 mmol). The mixture was stirred at RT overnight, and quenched withsaturated NH₄Cl solution. The solution was separated and the aqueous wasextracted with DCM (3×100 mL). The combined organic layers were washedwith water, dried (MgSO₄), filtered, and concentrated under vacuum togive red yellowish solid 7A (9.13 g, yield: 98%).

To compound 7A (4.55 g, 9.06 mmol) in MeOH/EtOAc (400 mL, 1:1) in ahydrogenation bottle was added 10% Pd—C (1 g). The reaction vessel wasshaken in the Parr shaker under 50 psi hydrogen for 4 h. Then thecatalyst was filtered off through a celite bed and washed with MeOH andEtOAc. The filtrate was concentrated under vacuum to give white solid 7B(3.81 g, 89%).

Following the approach outlined in Example 6 (Steps 1-2), 7B was treatedwith Ac₂O/HCO₂H and then reduced with BH₃—SMe₂ to afford 7C. In a mannersimilar to that found in Example 5 (Steps 3-4), 7C was furtherelaborated by treatment with EtNCO and deprotection with TFA to providethe title compound 7. MS m/z 316 (MH+).

Preparative Example 8

To compound 7C (1.5 g, 3.09 mmol) in anhydrous DCM (10 mL) was addedpyridine (0.5 mL, 6.18 mmol) and ClCO₂Et (0.59 mL, 6.18 mmol)sequentially. The mixture was stirred at RT overnight, and then quenchedwith saturated NH₄Cl solution. The solution was concentrated and theaqueous was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine, dried (MgSO₄), filtered, and concentrated undervacuum.

The residue was then deprotected with TFA, in a manner described inExample 5, Step 4, to afford compound 8 (145 mg, 15% for two steps). MSm/z 317 (MH+).

Preparative Example 9

The synthesis in Example 9 used starting materials 9A, 9B or 9C.Compound 9B can be synthesized from 9A by using reduction method A or B:

Method A: To compound 9A in MeOH was added 10% Pd/C and the mixture wasstirred at RT under hydrogen balloon overnight. Then the catalyst wasfiltered off through a celite bed and washed with MeOH. The filtrate wasconcentrated to give compound 9B for next reaction without furtherpurification.

Method B: To compound 9A in EtOH was added SnCl₂-2H₂O (4 eq.), and themixture was heated to reflux for 2 h. The mixture was concentrated andpoured into ice, neutralized to pH 7 with sat. NaHCO₃. Then the solidwas filter off and washed extensively with EtOAc. The filtrate wasseparated and the aqueous was extracted with (3×). The organic layer wasdried (MgSO₄), filtered and concentrated to give compound 9B.

Compounds 9E-9Z (shown in Table 3) were synthesized starting from 9A, 9Bor 9C by following the procedures described in Example 3. The selectivesingle-nitro reduction of starting material 9A13 (2,6-dinitrophenol)using Method A provided 2-amino-6-nitrophenol.

TABLE 3 Reduction Starting method Spectral data Material R from 9A CpdMS (MH+) unless noted 9A1 4-F A 9E 234 9A2 5-F A 9F 234 9A3 6-F A 9G 2349A4 5,6-diF A 9H 252 9B1 4-Cl N.A. 9I ¹H NMR (CDCl₃): 7.60 (s, 1H), 6.90(s, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 6.55 (dd, 1H), 4.40 (s, 2H), 4.20(t, 2H), 3.40 (t, 2H) 9B2 5-Cl N.A. 9J 250 9A5 6-Cl B 9K 250 9A64,6-diCl B 9L 284 9C1 4-Me N.A. 9M 230 9A7 3-Me A 9N 230 9B3 4-Ph N.A.9O 292 9A8 4-Br B 9P 294 9A9 4-CF₃ A 9Q 284 9A10 3-OMe A 9R 246 9A114-OMe A 9S 246 9B4 5-OMe N.A. 9T 246 9A12 6-OMe A 9U 246 9B5 4-SO₂NH₂N.A. 9V 295 9B6 4-SO₂Et N.A. 9W 308 9B7 5-NO₂ N.A. 9X 261 9A13 6-NO₂ A9Y 261 9A14 4-CO₂CH₃ B 9Z 274

Starting Material 9A10 in Table 3 was Prepared as Follows:

Dimethylsulfate (2.7 mL, 0.058 mmol) was added carefully to2-nitrobenzene-1,3-diol (2.5 g, 0.232 mmol) and the mixture was stirredvigorously while 10% NaOH solution (21 mL) was added and the temperaturewas kept below 40° C. After about 15 min, the mixture was cooled andthen filtered. The filtrate was collected and acidified with 10% HCl,and extracted with ether (3×25 mL). The organic layer was dried (MgSO₄),filtered, and concentrated under vacuum. Chromatography (10-30%EtOAc/hexanes) provided 9A10 (1 g, 37%).

Starting Material 9A12 in Table 3 was Prepared as Follows:

Fuming HNO₃ (0.34 mL, 0.008 mmol) was carefully added to a mixture of2-methoxyphenol (0.886 mL, 0.008 mmol) in anhydrous DCM (10 mL) at −20°C. After stirring for 2 h at RT, the mixture was concentrated undervacuum. Chromatography (10-30% EtOAc/hexanes) provided 9A12 (400 mg,29%) and 2-methoxy-3-nitrophenol (400 mg, 29%).

Preparative Example 10

A mixture of compound 9Z (46 mg, 0.24 mmol) in anhydrous THF (10 mL) at0° C. was carefully treated with LAH powder (18 mg, 0.48 mmol) and thenstirred for 2 h at RT. The reaction was quenched with 1N NaOH solution(2 mL), filtered and concentrated under vacuum. Chromatography (DCM with3 to 5% of 7N NH₃-MeOH) provided 10 (47 mg, 80%). MS m/z 246(MH+).

Preparative Example 11

A mixture of 9Z (67 mg, 0.24 mmol) in MeOH (5 mL) was treated with NaOH(15 mg, 0.38 mmol) and stirred at RT overnight. The reaction was thenneutralized with 10% HCl and concentrated under vacuum. The residue wastaken up in MeOH, stirred for 1 h, filtered, and concentrated.Chromatography (Prep-HPLC) provided compound 11 (21 mg, 32%). MS m/z260(MH+).

Preparative Example 12

A mixture of 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (9D, 1.5 g, 7.05mmol) and CuCN (1.58 g, 17.61 mmol) in anhydrous DMF (15 mL) was stirredat 130° C. for 3 h and then at 150° C. overnight. Then the mixture wascooled to RT, quenched with water and concentrated under vacuum. Theresidue was taken up in 2N NaOH and EtOAc (100 mL) and then agitated ina sonicator for 1 h. The precipitate was filtered off and washed withEtOAc. The filtrate and washings were combined and extracted with EtOAc(2×80 mL). The organic layer was dried (MgSO₄), filtered andconcentrated under vacuum to give compound 12A (1.062 g, 94%).

Step 2

In a manner similar to that found in Example 3, Step 3, 12A wasconverted to the title compound 12. MS m/z 241 (MH+).

Example 13

A solution of 12 (0.179 g, 0.75 mmol) in anhydrous EtOH (10 mL) wascooled to 0° C. and treated with bubbling HCl gas for 15 min. Themixture was stirred at 0° C. for 30 min, warmed to RT overnight, andconcentrated. The residue was dissolved in 2.0 M NH₃-MeOH (5 mL),stirred at RT for 4 h, and then concentrated under vacuum.Chromatography (Ranin-Prep HPLC, Waters SunFire™ Prep C18 5 μM, 19-100mm column, 5-90% CH₃CN/H₂O gradient) gave the compound 13 (36 mg: 19%).MS m/z 258 (MH+).

Preparative Example 14

To a suspension of KH (30% in mineral oil, washed with hexanes, 1.2 g,8.98 mmol) in anhydrous THF (20 mL) at 0° C. under argon was added asolution of 6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 1.02 g, 4.49 mmol) inTHF (20 mL). After 15 min, the solution was cooled to −78° C., andt-BuLi (1.7 M in pentane, 5.18 mL, 8.8 mmol) was added dropwise. Themixture was stirred for 15 min at −78° C., and then treated withdimethyl disulfide dropwise. The solution was warmed gradually to RT andstirred overnight. The reaction was then quenched by sat. NH₄Cl (15 mL)carefully, and filtered. The filtrate was diluted with water andextracted with EtOAc (3×50 mL). The combined organic layers were dried(MgSO₄), filtered, and concentrated. Chromatography (5-25% EtOAc/hexanes) provided 14A (0.483 g, 55%).

In a manner similar to that found in Example 3, Steps 2-3, 14A wasreduced with BH₃—SMe₂ and treated with imidazole-4-carboxaldehyde toprovide 14B. MS m/z 262(MH+).

To compound 14B (0.447 g, 1.71 mmol) in anhydrous DCM (10 mL) was addedMCPBA (77%, 0.85 g, 3.77 mmol), and the mixture was stirred at RTovernight. The reaction was quenched with sat. Na₂CO₃ solution and thesolvent was removed under vacuum. The concentrated solution wasextracted with EtOAc (3×10 mL). The organic layer was dried (MgSO₄),filtered, and concentrated under vacuum. Chromatography (DCM containing1-7% of 7N NH₃-MeOH) provided the title compound 14 (67 mg, 13%, MS m/z294 MH+) and a mixture of 14C and 14, which was purified byRanin-preparative HPLC to provided 14C (39 mg, 8%, MS m/z 278 MH+).

Preparative Example 15

To compound 6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 500 mg, 2.2 mmol) intoluene (44 mL) was added Pd(PPh₃)₄ (127 mg, 0.11 mmol). After stirringat RT for 30 min, boronic acid 15A (697 mg, 3.3 mmol) in EtOH (13 mL,0.25 M) and saturated NaHCO₃ solution (22 mL) were added and thesolution was heated to reflux overnight. Then the mixture was cooled toRT, and poured into saturated NaCl solution, and concentrated undervacuum. The residue was diluted with water and extracted with EtOAc(3×25 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated under vacuum. Chromatography (10 to 30% EtOAc/hexanes)provided 15B (320 mg, 46%).

In a manner similar to that found in Example 3, Steps 2-3, 15B wasreduced with BH₃—SMe₂ and treated with imidazole-4-carboxaldehyde toprovide 15C. MS m/z 381 (MH+).

Step 4

A mixture of 15C (143 mg, 0.37 mmol) in 4.0M HCl-dioxane (1.5 mL, 0.56mmol) was stirred at RT overnight. The reaction was neutralized with 7NNH₃-MeOH and concentrated. The residue was purified by preparative TLC(DCM containing 10% of 7N NH₃-MeOH) to provide the title compound 15 (28mg, 26%). MS m/z 281 (MH+).

Preparative Example 16

To a stirred solution of Pd (OAc)₂ (3 mg, 0.0125 mmol) and PPh₃ (13 mg,0.05 mmol) in anhydrous THF (2 mL) under argon was added6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 57 mg, 0.25 mmol). The mixturewas stirred at RT for 10 min and treated sequentially with a solution of3-pyridine boronic acid (62 mg, 0.5 mmol) in EtOH (1 mL) and aqueousNaHCO₃ solution (2 M, 2 mL). The mixture was heated to reflux for 2 hand then cooled to RT. The solution was poured into saturated NaClsolution, and then concentrated under vacuum. The residue was dilutedwith water (5 mL) and extracted with EtOAC (3×10 mL). The organic layerwas dried (MgSO₄), filtered, and concentrated under vacuum.Chromatography (10-30% EtOAc/hexanes) provided 16A (21 mg, 37%).

Steps 2-3

Compound 16A was converted to compound 16 by reduction with BH₃-SMe₂ andreductive alkylation with imidazole-4-carboxaldehyde as described inExample 3, Steps 2-3. MS m/z 293(MH+).

Preparative Example 17

A Smith process vial (2-5 mL) was charged with a stir bar,6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 23 mg, 0.1 mmol),thiophen-3-ylboronic acid (17 mg, 0.13 mmol) and EtOH (2 mL). AqueousK₂CO₃ (1 M, 0.12 mL) and polymer-supported Pd (40 mg, 3 mol % Pd,FiberCat. 1000-D32, Pd% 4.26) were then added sequentially. The reactionvessel was sealed and heated to 110° C. for 1 h under microwaveirradiation. After cooling, the reaction mixture was transferred to aprepacked column of Si-carbonate (2 g, 0.79 mmol/g), which had beenconditioned with MeOH/DCM (1:1). The product was eluted with MeOH/DCM(1:1, 3×3 mL, gravity filtration) and concentrated to give compound 17A(18 mg, 80%).

Steps 2-3

Compound 17A was converted to 17 in a manner similar to that found inExample 3, Steps 2-3. MS m/z 298 (MH+).

Preparative Example 18

A Smith process vial (20 mL) was charged with a stir bar, compound 3A (1g, 6.49 mmol), ethyl 2-bromo-2-methylpropanoate (1 mL, 6.81 mmol), KF(1.13 g, 19.5 mmol) and DMF (10 mL). The reaction vessel was sealed andheated to 160° C. for 1 h under microwave irradiation. After cooling,the reaction mixture was poured into ice-water and extracted with EtOAc(3×50 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated under vacuum. Chromatography (10-30% EtOAc/hexanes) gave18A (0.245 g, 17%).

In a manner similar to that found in Example 3, Steps 2-3, 18A wasreduced with BH₃-SMe₂ and reacted with imidazole-4-carboxaldehyde toprovide 18B. MS m/z 289 (MH+).

Following the procedure found in Example 3, Step 4, 18B was hydrogenatedto give compound 18C. In a manner similar to that found in Example 3,Step 5, 18C was further reacted with ClCO₂Me to provide the titlecompound 18. MS m/z 317 (MH+).

Preparative Example 19

To 2-fluorophenol (19A, 8 mL, 86.4 mmol) in anhydrous DCM (70 mL) at 0°C. was added fuming HNO₃ (0.34 mL, 0.008 mmol) dropwise through anaddition funnel. The mixture was warmed to RT and stirred for 2 h, thencooled to 0° C. again and quenched with 2N NaOH solution to pH 5. Themixture was concentrated under vacuum, diluted with water, extractedwith EtOAc (3×100 mL). The combined organic layer was dried (MgSO₄),filtered, and concentrated under vacuum to give compound 19B (15.07 g,yield: 86.4%).

A solution of 19B (15.07 g, 74.6 mmol) in EtOH (300 mL) was treated withSnCl₂-2H₂O (50.5 g, 224 mmol) and heated to reflux for 2 h. The mixturewas concentrated, poured into ice, and neutralized to pH 7 with 2N NaOHsolution. The solid was filtered off and washed with EtOAc (5×500 mL).The filtrate was separated and the aqueous was extracted with EtOAc(3×100 mL). The organic layer was dried (MgSO₄), filtered andconcentrated under afford 19C (12.59 g, 98%).

In a manner similar to that found in Example 3, Steps 1-3, 19C wasreacted with chloroacetyl chloride, reduced with BH₃—SMe₂, and treatedwith imidazole-4-carboxaldehyde to provide compound 19D. MS m/z 279(MH+).

In a manner similar to that found in Example 3, Step 4, 19D washydrogenated to afford compound 19E. MS m/z 249 (MH+). Compound 19E wasfurther reacted with ClCO₂Me as described in Example 3, Step 5, toprovide the title compound 19. MS m/z 307 (MH+).

Preparative Example 20

To 2-chloro-4,6-dinitrophenol (20A, 2 g, 9.18 mmol) in EtOH (100 mL) wasadded a scoop of Raney nickel (20% by weight) carefully. The mixture wasstirred at RT under hydrogen balloon overnight and then filtered. Thesolvent was evaporated off under vacuum to give white solid 20B (1.3 g,89%) and used directly in the next reaction.

Following the procedure described in example 3, Step 1, 20B was reactedwith chloroacetyl chloride to provide 20C (5%). Compound 20C was treatedwith ClCO₂Me, reduced with BH₃—SMe₂, and reductively alklyated in amanner similar to that found in Example 8 and Example 3 (Steps 2-3) toafford the title compound 20. MS m/z 323 (MH+).

Preparative Example 21

To compound 21A (5 g, 30 mmol) in concentrated H₂SO₄ (17 mL) was added a1:1 mixture of fuming HNO₃ and conc. H₂SO₄ (7 mL) over 15 min. Themixture was stirred for additional 30 min at RT and was slowly pouredinto ice water (500 mL). The mixture was filtered to collect solid andwashed with water (4×). The solid was placed under high vacuum in an 80°C. oil bath for 5 h to provide 21 B (3.82 g, 60%).

In a manner similar to that found in Example 3, Steps 2-3, 21 B wasreduced with BH₃—SMe₂ and then treated with imidazole-4-carboxaldehye toafford compound 21C. MS m/z 279 (MH+).

In a manner similar to that found in Example 3, Steps 4, 21C washydrogenated to provide compound 21D. Compound 21D was then converted tothe title compound 21 as described in Example 3, Step 5. MS m/z 307(MH+).

Preparative Example 22

Following the procedures described in Example 21 (Step 1) and Example 3(Steps 2-3), 22A was nitrated with HNO₃, reduced with BH₃—SMe₂, andreacted with imidazle-4-carboxaldehyde to provide compound 22. MS m/z262 (MH+).

Preparative Example 23

A solution of compound 23A (330 mg, 2.2 mmol, U.S. Pat. No. 5,652,363)in DMF (4 mL) was treated with NaH (60% in mineral oil, 88 mg, 2.2 mmol)at RT. The mixture was stirred for 20 min, followed by addition of asolution of compound 23B (0.79 g, 2.2 mmol, J. Med. Chem., 2002, 45,533) in DMF (4 mL). The mixture was stirred at 45° C. for 3 days, andthen quenched with water and concentrated under vacuum. The residue wasdissolved in EtOAc (50 mL), washed with water (2×10 mL). The organiclayer was dried (Na₂SO₄), filtered, and concentrated under vacuum.Chromatography (DCM with 2-3% 7 N NH₃-MeOH) provided 23C (519 mg, 50%).MS m/z 473 (MH+).

Steps 2-3

In a manner similar to that found in Example 2 (Step 2) and Example 15(Step 4), 23C was reduced with BH₂—SMe₂ (18 h at reflux) and thendeprotected with HCl-dioxane (1 h at 60° C.) to provide the titlecompound 23. MS m/z 217 (MH+).

Preparative Example 24

A stirred solution of 2-chloro-5-nitroaniline 24A (34.4 g, 0.2 mol) inabsolute EtOH (200 mL) at 70° C. was treated gradually with a solutionof sodium sulfide nonahydrate (48 g, 0.2 mol) and sulfur (9.6 g, 0.3mol), which had been preheated to melting. The mixture was refluxed for30 min and cooled to RT. The mixture was filtered to collect the solid,wash with water. The solid was dried under vacuum at 100° C. for 5 h.The resulting solid was taken up in water (200 mL) and treated with NaOH(8 g, 0.2 mol) and ClCH₂COOH (18.9 g, 0.2 mol). The mixture was thenheated to reflux for 1.5 h. After cooling down, the mixture wasacidified with 10% HCl solution and filtered to collect brown-yellowsolid, and washed with water to give compound 24B (25 g, 60%).

Following the procedure described in Example 3, Steps 2-3, 24B wasreduced with BH₃—SMe₂ and treated with imidazole-4-carboxaldehyde toprovide 24C. MS m/z 277 (MH+).

In a manner similar to that found in Example 3, Step 4, 24C washydrogenated to provide 24D. MS m/z 247 (MH+). Compound 24D was furthertreated with ClCO₂Me as described in Example 3, Step 5, to provide thetitle compound 24. MS m/z 305 (MH+).

Preparative Example 25

Following procedures described in Example 3 (Steps 2-3), compound 25Awas subjected to reduction with BH₃—SMe₂ and then reductive aminationwith imidazole-4-carboxaldehyde to provide compound 25B. MS m/z 232(MH+).

In a manner similar to that found in Example 14, Step 4, 25B wasoxidized with MCPBA to the afford compounds 25C (MS m/z 248 MH+) and 25(MS m/z 264 MH+).

Preparative Example 26

In a manner similar to that found in Example 1,1,2,3,4-tetrahydro-quinoxaline and imidazole-4-carboxaldehye 1Bunderwent reductive amination to provide 26A. LMCS m/z 215 (MH+).

In a manner similar to that found in Example 3, Step 5, 26A wasconverted to 26B. LMCS m/z 273 (MH+).

Step 3

Compound 26B (120 mg) was added portionwise to a stirred slurry of LAHpowder (500 mg) in Et₂O (15 mL) at 0° C. The mixture was refluxed for 1h and then cooled to 0° C. The reaction was treated sequentially withH₂O (0.5 mL), 1 N NaOH (0.5 mL), and H₂O (1.5 mL). and thenconcentrated. Chromatography (DCM with 2 to 5% of 7N NH₃-MeOH) providedthe title compound 26. MS m/z 229(MH+). Alternatively, compounds in thisclass may be synthesized by a solid phase approach as described in thefollowing Example 27.

Preparative Example 27

A mixture of 1,2,3,4-tetrahydroquinoxaline (27A, 2 g, 14.9 mmol) indioxane (15 mL) and water (24 mL) at 0° C. was sequentially treated withNa₂CO₃ (1.58 g, 14.9 mmol) and FmocCl (3.84 g, 14.9 mmol) in dioxane (20mL, added dropwise). The mixture was warmed to RT gradually and stirredovernight. The reaction mixture was diluted with water (50 mL) andextracted with DCM (2×70 mL). The combined organic layers were dried(Na₂SO₄), concentrated, and subjected to chromatography (30-40%EtOAc/hexanes, yields 0.75 g, 14%). Subsequent reaction with resin 1D asdescribed in Example 1 provided 27B.

Compound 27B (0.5 g, 1.4 mmol/g) was stirred in 30% piperidine/DMFovernight. The resin was washed with DMF (3×), MeOH (3×) and DCM andthen dried in vacuo to provide 27C. Resin 27C (125 mg, 1.4 mmol/g) wassuspended in DCM (5 mL) and treated with pyridine (0.283 mL, 3.5 mmol)and MeSO₂Cl (0.135 mL, 1.75 mmol). The reaction was shaken overnight,then washed with MeOH (2×), DMF (2×), DCM (2×), MeOH (2×) and DCM (3×).Subsequent cleavage from the resin with TFA, as described in Example 1,provided the title compound 27. MS m/z 293 (MH+).

Compounds in Table 4 can be prepared from Resin 27C by reaction with thevarious reagents shown followed by TFA cleavage.

TABLE 4

Cpd Reagent R MS (MH+) 27D Me₂NSO₂Cl/ pyridine

322 27E Ac₂O/ pyridine

257 27F MeNCO

272

Preparative Example 28

To 6-nitro-2-aminophenol (3A, 3.03 g, 19.7 mmol) in anhydrous DCM (50mL) was added dipyridylcarbonate (4.25 g, 19.7 mmol). The mixture wasstirred at RT overnight, and then concentrated under vacuum.Chromatography (1-6% MeOH/DCM) afforded the solid 28A (2.77 g, 78%).

A solution of 28A (0.69 g, 3.83 mmol) in 2-ethoxyethanol (10 mL) wastreated with KOH (0.22 g, 3.83 mmol) and stirred at RT for 1 h. Themixture was then heated to reflux and treated with1-bromo-3-chloropropane (0.75 mL, 7.67 mmol). After refluxing for 4 h,the solution was filtered and concentrated to provide 28B, which wastaken on to Step 3 without further purification.

A solution of 28B in 2-ethoxyethanol and DMF (10 mL, 1:1) wastransferred into a Smith process vial (20 mL) with a stir bar, andtreated with KOH (0.86 g, 15.32 mmol). The reaction vessel was sealedand heated to 220° C. for 1 h under microwave irradiation. Aftercooling, the reaction mixture was filtered and concentrated. The residuewas diluted with water and extracted with EtOAc (3×10 L). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated undervacuum. Chromatography (DCM containing 1-5% 7N NH₃-MeOH) provided 28C(124 mg, 17% for 2 steps).

In a manner similar to that found in Example 3 (Step 3), 28C was reactedwith imidazole-4-carboxyaldehyde to provide compound 28D. MS m/z 275(MH+).

In a manner similar to that found in Example 3 (Step 4), 28D washydrogenated to afford compound 28E. MS m/z 245 (MH+). Following theprocedure found in Example 3 (Step 5), 28E was further reacted withClCO₂Me to provide the title compound 28. MS m/z 303 (MH+).

Preparative Example 29

A mixture of 4-hydroxy-3-nitrophenylacetic acid (10 g, 51 mmol) and 4MHCl-dioxane (40 mL) in EtOH (150 mL) was refluxed for 2 h andconcentrated. The residue was then taken up in 1 N NaOH (50 mL) andextracted with CH₂Cl₂ (8×). The combined organic layers were dried overNa₂SO₄, and concentrated to provide 29A (8.39 g, 73%) as a yellow oil.

In a manner similar to that described in Example 20 (Step 1) and Example3 (Step 1), 29A was hydrogenated with Raney Ni (50 psi H₂) and thencyclized with chloroacetyl chloride to provide 29B. Compound 29B couldbe further elaborated to the title compound 29 following the proceduredetailed in Example 3 (Steps 2-3). LMCS m/z 302 (MH+).

Preparative Example 30

A stirred solution of benyzlamine (0.070 mL, 0.66 mmol) in CH₂Cl₂ (10mL) was treated dropwise with AlMe₃ (2M/toluene, 0.33 mL, 0.66 mmol) at20° C. After 20 min, a solution of 29 (0.10 g, 0.33 mmol) in CH₂Cl₂ (3mL) was added slowly. The mixture was then heated at reflux overnightand cooled to 20° C. The reaction was quenched with H₂O (0.5 mL), andstirred 1h. The mixture was then dried with Na₂SO₄, filtered, andconcentrated. Chromatography (2-5% 1 N NH₃-MeOH/CH₂Cl₂) provided 30 as awhite film (0.115 g, 96%). LMCS m/z 363 (MH+).

Preparative Example 31

In a manner similar to that found in Example 26 (Step 3) and Example 1,29B was reduced with LAH and then treated withimidazole-4-carboxaldehyde to provide 31A. LMCS m/z 260 (MH+).

Step 3

A solution of 31A (0.20 g, 77 mmol) in 1,2-dichloroethane (10 mL) wastreated with Et₃N (0.20 mL, 1.5 mmol) and MeNCO (0.050 mL, 0.85 mmol)and stirred for 3 h at 20° C. The mixture was treated with H₂O (10 mL),extracted with CH₂Cl₂ (2×), and concentrated. The residue was subjectedto chromatography (2-5% MeoH/CH₂Cl₂) and then stirred in Et₂NH (5 mL) at20° C. overnight. The mixture was concentrated, treated with 1 N NaOH,and extracted with CH₂Cl₂ (3×). The combined organic extracts were driedwith Na₂SO₄, and concentrated. Chromatography (5% MeOH/CH₂Cl₂) provided31 as a white film (0.080 g, 33%). LMCS m/z 317 (MH+).

Preparative Example 32

Following the procedures found in Example 20 (Step 1) and Example 3(Step 1), 32A was hydrogenated with Raney Ni (50 psi H₂) and thencyclized with chloroacetyl chloride to provide 32B.

Following the procedure found in Example 26 (Step 3), the nitrile andamide found in compound 32B were concomitantly reduced with LAH. Theresultant product (0.83 g, 5.1 mmol) in CH₂Cl₂ (50 mL) was treated withBOC₂O (1.07 g, 5.1 mmol), stirred at 20° C. for 0.5 h and thenconcentrated. Chromatography (20-50% EtOAc/hexanes) provided 32C as awhite sticky foam (1.19 g, 89%)

In a manner similar to that found in Example 1 and Example 15 (Step 4),32C was treated with imidazole-4-carboxaldehyde and then deprotected toafford 32D. LMCS m/z 245 (MH+). Following the procedure describedExample 3, Step 5, 32D was treated with ClCO₂Me and converted to thetitle compound 32. LMCS m/z 303 (MH+).

Preparative Example 33

In a manner similar to that found in Example 3 (Step 1) and Example 26(Step 3), 2-amino-3-hydroxypyridine was cyclized with chloroacetylchloride and then reduced with LAH to afford 33A.

A solution of 33A (0.105 g 0.77 mmol) in DMF (5 mL) was treated withKN(SiMe₃)₂ (0.5 M/toluene, 1.8 mL, 0.93 mmol), stirred at 0° C. for 20min, and then treated with 33B (0.155 g 1.16 mmol, Tetrahedron Letters2000, 41, 8661). The reaction was warmed to 20° C., stirred 2 h, andconcentrated. The residue was then treated with 0.5 N NaOH (10 mL) andwashed with CH₂Cl₂ (3×). The aqueous layer was concentrated andsubjected to chromatography (20-80% EtOAc/hexanes) to provide 33 as awhite solid (0.065 g, 36%). LMCS m/z 234 (MH+).

Preparative Example 34

A mixture of 2-chloro-3-nitropyridine (9.4 g, 59 mmol), glycine ethylester hydrochloride (10.8 g, 77 mmol), and K₂CO₃ (21.3 g, 154 mmol) intoluene (100 mL) was refluxed overnight. The mixture was then filtered,concentrated, and subjected to chromatography (20% EtOAc/hexanes). Theresulting yellow solid was dissolved in EtOH (300 mL), treated withRaney Ni (2 g) and hydrogenated at 40 psi H₂ overnight. The mixture wasfiltered, concentrated and chromatographed (2-5% MeOH/CH₂Cl₂) to provide34A (1.25 g, 14%) and N-(3-amino-2-pyridinyl)glycine ethyl ester (8.2 g,71%).

In a manner similar to that found in Example 5 (Step 1), 34A wasconverted to 34B (BOC₂O, DMAP and Et₃N in refluxing DCM).

In a manner similar to that found in Example 26 (Step 3), 34B wastreated with LAH to provide 34C as a white solid (0.040 g, 48%).Following the procedure found in Example 1, 34C was then treated withimidazole-4-carboxaldehyde to provide the title compound 34. LMCS m/z230 (MH+).

Preparative Example 35

A solution of 34A (0.260 g, 1.74 mmol) in THF (15 mL) was treated withEt₃N (1.2 mL, 8.7 mmol) and Ac₂O (0.33 mL, 3.5 mmol) and stirredovernight at 20° C. The reaction was treated diluted with H₂O (10 mL)and extracted with 10% MeOH/CH₂Cl₂ (3×). The combined organic extractswere dried with Na₂SO₄ and concentrated. Chromatography (20-50%EtOAc/hexanes) provided 35A as a white solid (0.140 g, 42%).

In a manner similar to that found in Example 26 (Step 3) and Example 1,35A was reduced with LAH and then treated withimidazole-4-carboxaldehyde to provide the title compound 35. LMCS m/z244 (MH+).

Preparative Example 36

A solution of 34A (0.200 g 1.33 mmol) in DMF (15 mL) was treated withKN(SiMe₃)₂ (0.5M/toluene, 3.2 mL, 0.93 mmol), stirred at 0° C. for 30min, and then treated with CH₃I (0.12 mL, 2.00 mmol). The reaction waswarmed to 20° C., stirred overnight, and concentrated. The residue wasthen treated with 0.5 N NaOH (10 mL) and extracted with CH₂Cl₂ (3×). Thecombined organic layers were concentrated and subjected tochromatography (2-5% MeOH/CH₂Cl₂) to provide 36A (0.120 g, 55%).

In a manner similar to that found in Example 26 (Step 3) and Example 1,36A was reduced with LAH and then reacted withimidazole-4-carboxaldehyde to provide 36. LMCS m/z 230 (MH+).

Preparative Example 37

A mixture of 3C (2 g, 11.1 mmol) in anhydrous DMF (20 mL) was treatedwith 2-(1H-imidazol-4-yl)acetic acid (2 g, 17.5 mmol), HATU (6.2 g, 16.3mmol) and DIEA (0.4 mL, 2.3 mmol) at 25° C. The mixture was stirred atroom temperature overnight and then concentrated under vacuum. Columnchromatography (DCM containing 1-6% of 7N NH₃/MeOH) provided 37A (1.2 g,yield: 38%). In a manner similar to Example 2, Step 2, compound 37A wasreduced with BH₃—SMe₂ to provide compound 37. MS m/z 275 (MH+).

Preparative Example 38

A solution of compound 3C (14.1 g, 78 mmol) in MeCN (200 mL) was treatedwith (BOC)₂O (20.5 g, 94 mmol) and DMAP (0.5 g) and then refluxedovernight. The reaction mixture was concentrated and chromatographed(10% -50% EtOAc/hexanes) to give compound 38A (16.1 g, 74%, typically70-90%) and recovered starting material 3C.

A mixture of compound 38A (16.1 g, 58 mmol) in EtOH (300 ml) was treatedwith Raney Ni (˜5 g) and hydrogenated (40 psi H₂) overnight. Thereaction mixture was filtered and concentrated.

The resulting white solid (˜15.3 g, 61 mmol) was suspended in anhydrousTHF (200 mL) and treated slowly with Ac₂O (˜18 mL, 173 mmol). Afterstirring for 2 h at 20° C., the reaction mixture was concentrated invacuo and taken up in 25% aqueous NaOH (100 mL) and CH₂Cl₂. The layerswere separated. The aqueous layer was further extracted with CH₂Cl₂(3×). The organic layers were combined, dried with Na₂SO₄, and filteredto give 38B as a gray solid (17.6 g, quantitative yield).

A solution of compound 38B (21 g, 72 mmol) in THF (300 ml) at 0° C. wasslowly treated with BH₃-DMS (60 ml, 2M/THF) and then heated to refluxovernight. The mixture was concentrated, treated with K₂CO₃ (9.9 g) andEtOH (300 mL) and then refluxed for 45 min. The reaction mixture wasfiltered, concentrated, added to H₂O and extracted with CH₂Cl₂ (4×). Thecombined organic layers were dried with Na₂SO₄, filtered andconcentrated.

The resulting clear oil (21.9 g) was dissolved in anhydrous CH₂Cl₂ (300ml), treated slowly with MeNCO (˜5 g, 86 mmol), and then stirred at RTfor 30 min. The reaction mixture was concentrated and chromatographed(50%-80% EtOAc/hexanes) to give the product 38C as a white solid (21.65g, 90% yield for two steps).

Steps 6-7

A solution of compound 38C (21.65 g, 65 mmol) in of CH₂Cl₂ (300 ml) wastreated with TFA (100 mL) and refluxed for 0.5 h. The reaction mixturewas concentrated, treated with 20% NaOH (150 mL) and extracted withCH₂Cl₂ (4×). The combined organic layers were dried with Na₂SO₄,filtered and concentrated to give a white solid (14.23 g, ˜93%).

The crude product (16.2 g, 68.9 mmol) was combined with4-imidazolecarboxaldehyde (1B, 6.6 g, 68.9 mmol) and Ti(OiPr)₄ (25 mL,86 mmol) in CH₂Cl₂ (15 ml) and stirred at RT until the reaction mixturebecame clear (˜1 h). Following the addition of NaBH₄ (3.3 g, 86 mmol)and EtOH (200 mL), the reaction was stirred at RT overnight andconcentrated. The residue was taken up in 0.5 N NaOH and extracted withCH₂Cl₂ (4×). The combined organic layers were dried with Na₂SO₄,filtered, and concentrated. Chromatography (5-10% of 7N NH₃—MeOH inCH₂Cl₂) provided compound 38 (14.13 g, 68%) as a white solid.

Preparative Example 39

Bromine (8.0 g, 50 mmol, 2.3 eq) in anhydrous Ac₂O (40 mL) was addeddropwise to a solution of 1B (2.08 g, 21.7 mmol) and NaOAc (18.7 g, 228mmol, 10.5 eq) in anhydrous HOAc (200 mL) over a period of 1 h at RT.The resulting mixture was stirred at RT for 2.5 h and then concentrated.The residue was partitioned between Et₂O (200 mL) and water (200 mL),the layers were separated and the aqueous layer was extracted with Et₂O(200 mL). The combined organic phase was dried, concentrated andchromatographed (EtOAc) to afford 5-bromo-4-formyl imidazole 39A (1.00g, 26%) as white crystals.

In a manner similar to that found in Example 1, 39A was treated with 39B(Example 6) to afford the title compound 39. LCMS m/z 280 (MH+).

Preparative Example 40

A mixture of 6 (0.25 g, 0.83 mmol) and NaHCO₃ (0.7 g, 8.3 mmol) in 1:1THF—H₂O (20 mL) was stirred vigorously for 10 min and then treated withphenyl chloroformate (PhOCOCl, 0.26 mL, 2.1 mmol). The reaction wasstirred at RT for 2 h and then diluted with EtOAc. The organic layer wasisolated, dried over Na₂SO₄ and concentrated. The resulting residue wasdissolved in MeOH, treated with Et₃N (0.6 mL, 4.3 mmol) and stirredovernight. The solution was concentrated and subjected to chromatography(5-10% NH₃—MeOH/EtOAc) to provide the title compound 40 as a lightyellow foam (0.2 g, 76%).

Preparative Example 41

A mixture of 1A (0.2 g, 1.5 mmol) and imidazole-4-carboxaldehyde (1B,0.16 g, 1.6 mmol) in CH₂Cl₂ (5 mL) was treated with Ti(OiPr)₄ (0.55 mL,1.88 mmol), stirred at RT overnight, and then treated with Et₂AlCN (2mL, 1M/toluene). After 18 h, EtOAc, H₂O, and celite were added.Filtration and subsequent chromatography (0-10% of 7N NH₃—MeOH inCH₂Cl₂) provided 41 as a yellow solid (0.178 g, 50%). LCMS m/z 241(MH+).

Preparative Example 42

In a manner similar to that found in Example 41, a mixture of 1A and 42A(Journal of Medicinal Chemistry, 1971, 14, 883) was treated sequentiallywith Ti(OiPr)₄ and Et₂AlCN to provide the compound 42B.

A solution of 42B (0.2 g, 0.41 mmol) in 1N NH₃—MeOH (50 mL) was treatedwith

Raney Ni and hydrogenated (50 psi H₂) overnight at RT. Filtration andsubsequent chromatography (0-7% of 7N NH₃—MeOH in CH₂Cl₂) provided 42Cas a yellow film (0.15 g, 74%).

A mixture of 42C (145 mg, 0.3 mmol) in CH₂Cl₂ (2 mL) was treated withTFA (0.5 mL) and Et₃SiH (0.05 mL). The reaction mixture was stirred atRT overnight and then concentrated. Chromatography (2-15% of 7 NNH₃—MeOH in CH₂Cl₂) provided the title compound 42 (69 mg, 95%) as ayellow oil. LCMS m/z 245 (MH+).

Preparative Example 43

In a manner similar to that described in Examples 19 and 3,2-cyanophenolwas subjected to bis-nitration with HNO₃, selective reduction withSnCl₂, cyclization with chloroacetyl chloride, and reduction withBH₃—SMe₂ to provide 43A.

A mixture of 43A (0.65 g, 3.2 mmol) and Et₃N (0.9 mL, 6.3 mmol) inCH₂Cl₂ (60 mL) was treated with Ac₂O (6 mL) and DMAP (0.15 g) and thenrefluxed for 2 d. The reaction was then cooled, washed with 1N HCl (2×),washed with brine, dried over Na₂SO₄, and concentrated. Chromatography(10-100% of EtOAc/hexanes) provided 43B as a yellow solid (0.688 g,88%).

In a manner similar to that described in Example 3 (Step 4), 43B washydrogenated with Pd/C.

A mixture of the aniline product (0.080 g, 0.38 mmol) in 6M HCl (0.5 mL)was treated with a solution of NaNO₂ (27 mg, 0.39 mmol) at 0° C. After0.5 h, the solution was neutralized with sat. aq. Na₂CO₃ and then addeddropwise to solution of CuCN (37 mg, 0.41 mmol) and NaCN (40 mg, 0.82mmol). The resulting mixture was stirred at 60° C. overnight and thenfiltered.

The brown precipitate (44 mg) was collected and then treated with 10%aq. NaOH (0.5 mL) for 2 h at RT. The reaction was then diluted with H₂Oand extracted with CH₂Cl₂ (3×). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated. Chromatography (20-100%of EtOAc/hexanes) provided 43C as a beige solid (0.0.15 g).

In a manner similar to that described in Example 3 (Step 3), 43C wasconverted to the title compound 43. LCMS m/z 266 (MH+).

Preparative Example 44

A solution of 4-phenylbutyl bromide (0.98 g, 4.6 mmol) and 44A (1.0 g,4.6 mmol) in 10 mL of benzene was treated sequentially with Bu₄NHSO₄(0.16 g, 0.46 mmol) and 50% aqueous NaOH (2.4 mL, 46 mmol, addedslowly). After stirring at RT under N₂ for 20 h, the solvent wasremoved. The reaction mixture was then diluted with H₂O, extracted withEtOAc, washed with H₂O (3×) and brine, dried over Na₂SO₄, and filtered.The filtrate was concentrated and chromatographed (5-10% EtOAc/hexanes)to provide 44B (0.7 g, 44%).

To a solution of 44B (0.2 g, 0.57 mmol) in 5 mL of CH₂Cl₂ (5 mL) wasadded TFA (1.5 mL). After stirring at RT for 1.5 h, the solution wascooled to 0° C. and treated with concentrated aqueous NH₃ (untilpH=10-11). The mixture was extracted with CH₂Cl₂, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to give an unstable amine (0.12g, 84%) which was immediately taken up in CH₂Cl₂ (8 mL) and treated withcompound 7B (0.21 g, 0.44 mmol) and Et₃N (0.17 mL, 1.2 mmol). After themixture was cooled to −50° C., triphosgene (0.04 g, 0.13 mmol) was addedto the solution. The mixture was stirred at −50° C. under N₂ for 1 h,then slowly warmed up to RT, and stirred under N₂ overnight. Afteradding 5% aqueous NaOH (10 mL), the products were extracted with CH₂Cl₂,dried over Na₂SO₄, and filtered. Chromatography (2% MeOH/EtOAc) provided44C (0.2 g, 67%).

Step 4

A mixture of 44C (0.13 g) in 3N HCl—MeOH (8 mL) was heated at 60° C.under N₂ for 1.5 h, cooled to 0° C. and neutralized with concentratedaqueous NH₃. The solution was concentrated, taken up in H₂O andextracted with CH₂Cl₂. The organic extract was dried over Na₂SO₄,filtered and chromatographed (5% NH₃—MeOH in CH₂Cl₂) to give the titlecompound 44 (0.05 g, 62%). LCMS m/z 506 (MH+).

Preparative Example 45

A solution of 4-phenylbutanol (2.50 g, 16.6 mmol) and 1,6-dibromohexane(8.12 g, 33.2 mmol) in anhydrous THF (30 mL) was treated slowly with NaH(1.0 g, 24.9 mmol) at RT. After refluxing under N₂ for 20 h, the mixturewas cooled to RT, and quenched with H₂O. The products were extractedwith ether, washed with brine, dried over Na₂SO₄, and filtered. Thefiltrate was concentrated and chromatographed (2% EtOAc/hexanes) to give45A (3.3 g, 63%).

To a solution of 45A (0.07 g, 0.21 mmol) and 7B (0.1 g, 0.21 mmol) intoluene (3 mL) and DMF (0.5 mL) was added DIPEA (0.07 mL, 0.42 mmol) atRT. After heating at 80° C. under N₂ for 20 h, the mixture wasconcentrated, taken up in CH₂Cl₂, washed with H₂O (3×) and brine, driedover Na₂SO₄, and filtered. Chromatography (60% EtOAc/hexanes) provided45B (0.04 g, 27%).

In a manner similar to that described in Example 5 (Step 3) and Example44 (Step 4), 45B was sequentially treated with MeNCO and HCl to providethe title compound 45. LCMS m/z 520 (MH+).

Preparative Example 46

Compound 46A (from Example 38, Step 2, 250 mg, 1 mmol) was taken up inDCE (10 mL) and treated sequentially with 2-methoxypropene (0.14 mL, 1.5mmol), HOAc (0.06 mL, 1.1 mmol), and NaBH(OAc)₃ (424 mg, 2.0 mmol). Thereaction mixture was stirred at RT overnight, quenched with 1.0 N NaOHand extracted with CH₂Cl₂ (3×20 mL). The combined organic layers werewashed with brine, dried, and then concentrated. Chromatography(EtOAc/hexanes) affored 46B (190 mg, 65%).

Steps 3-5

In a manner similar to that described in Example 38 (Steps 5-7), 46B wassequentially treated with MeNCO, deprotected with TFA, and treated with4-imdazolecarboxaldehyde to provide the title compound 46. LCMS m/z 330(MH+).

Preparative Example 47

A mixture of 46A (500 mg, 2 mmol) in CH₂Cl₂ (10 mL) was sequentiallytreated with methoxyacetyl chloride (0.22 mL, 2.4 mmol) and TEA (0.56mL, 4.0 mmol). The reaction mixture was stirred at RT overnight,quenched with sat. NaHCO₃, and extracted with CH₂Cl₂ (2×20 mL). Thecombined organic layers were washed with brine, dried, and concentrated.Chromatography (EtOAc/hexanes) afforded 47A (610 mg, 95%).

Steps 2-5

In a manner similar to that described in Example 38 (Steps 4-7), 47A wasreduced with BH₃—SMe_(e), treated with MeNCO, deprotected with TFA, andtreated with 4-imdazolecarboxaldehyde to provide the title compound 47.LCMS m/z 346 (MH+)

Preparative Example 48

A solution of 7B (140 mg, 0.3 mmol) in anhydrous CH₂Cl₂ (5 mL) wastreated with benzyl isocyanate (48 mg, 0.36 mmol). The reaction mixturewas stirred at RT overnight and then concentrated. Chromatographyafforded 48A (130 mg, 72%).

In a manner similar to that described in Example 42 (Step 3), 48A wasdeprotected with with TFA and Et₃SiH to provide the title compound 48.LCMS m/z 364 (MH+).

Preparative Example 49

A mixture of 7B (1.0 g, 2.12 mmol), benzyloxyacetic acid (0.46 g, 2.75mmol), EDCl (0.61 g, 3.18 mmol) and HOBt (0.42 g, 3.18 mmol) in DMF werestirred at RT for 1 d. The reaction was quenched with 0.5 N aq. NaOH (50mL) and extracted with CH₂Cl₂. The combined extracts were washed withbrine, dried (Na₂SO₄) and concentrated. Preparative TLC chromatography(5% NH₃—MeOH in CH₂Cl₂) provided 49A (0.52 g).

In a manner similar to that described in Example 42 (Step 3), 49A wasdeprotected with TFA and Et₃SiH to provide the title compound 49. LCMSm/z 379 (MH+).

Preparative Example 50

In a manner similar to that described in Example 5 (Steps 1-2) andExample 6 (Steps 1-2), compound 28C was converted to 50A.

A mixture of 50A (0.247 g, 0.99 mmol) in anhydrous DCM (5 mL) wastreated with carbonyldiimidazole (0.32 g, 1.97 mmol) and Et₃N (0.28 mL,1.97 mmol) and then stirred at RT overnight. The reaction was washedwith water and extracted with DCM (3×10 mL). The combined organic layerwas dried (MgSO₄), filtered, and concentrated under vacuum to givecompound 50B.

A solution of 50B was in anhydrous MeCN (5 mL) in a sealed tube wastreated with MeI (2 mL). The sealed reaction mixture was heated to 55°C. for 3 h, cooled to RT and concentrated. The residue was dissolved inanhydrous THF (5 mL) and then treated with MeONH₂—HCl (0.25 g, 2.97mmol) and DIEA (0.53 mL, 2.97 mmol). After stirring at RT overnight, thereaction was quenched with saturated NH₄Cl solution and concentratedunder vacuum. The residue was diluted with water and extracted withEtOAc (3×10 mL). The combined organic layer was dried (MgSO₄), filtered,and concentrated under vacuum to afford crude compound 50C (279 mg, 80%for 3 steps).

In a manner similar to that found in Example 5 (Step 4) and Example 3(Step 3), compound 50C was deprotected and converted to the titlecompound 50. MS m/z=332 (MH+).

Preparative Example 51

In a manner similar to that described in Example 21 (Step 1), Example 3(Step 2), Example 5 (Step 1) and Example 3 (Step 4), compound 22A wassequentially nitrated, reduced with BH₃—SMe₂, treated with Boc₂O, andhydrogenated to yield compound 51A.

Steps 5-7

In a manner similar to that described in Example 5 (Steps 3-5), 51A wastreated with MeNCO, deprotected with TFA, and converted to the titlecompound 51. MS m/z=289 (MH+).

Preparative Example 52

To a solution of 51A (740 mg, 2.95 mmol) in DCM (30 ml) was added4-nitrophenylchloroformate (891 mg, 4.42 mmol) and pyridine (0.48 ml,5.90 mmol). After stirring overnight at RT, TLC indicated consumption ofthe starting material. MeONH₂—HCl salt (739 mg, 8.84 mmol) in anhydrousTHF (10 ml) and DIEA (1.57 mL, 8.84 mmol) were then sequentially added.After stirring at RT overnight, the reaction was quenched by water,concentrated, diluted with water and extracted with EtOAc. The organicphase was dried (MgSO₄), filtered, and concentrated. Flashchromatography (20-50% of EtOAc/hexanes) provided 52A (650 mg, 68%).

In a manner similar to that found in Example 5 (Step 4) and Example 3(Step 3), 52A was converted to 52. MS m/z=305 (MH+).

Preparative Example 53

To compound 51A (100 mg, 0.40 mmol) in DCE (5 mL) was added acetaldehyde(0.045 mL, 0.80 mmol). The mixture was stirred at RT for 1 h and thentreated with MeOH (3 mL) and NaBH₄ (45.5 mg, 1.2 mmol). After stirringat RT overnight, the reaction was quenched by 2N NaOH solution,concentrated, diluted with water and extracted with EtOAc. The organicphase was dried (MgSO4), filtered, and concentrated under vacuum to givea residue 53A (40 mg, 36%).

In a manner similar to that found in Example 3 (Step 5), Example 5 (Step4) and Example 3 (Step 3), 53A was treated with ClCO₂Me/pyridine,deprotected with TFA and converted to the title compound 53. MS m/z=318(MH+).

Preparative Example 54

In a manner similar to that found in Example 3 (Step 2), compound 54A(see WO 2006/020561) was reduced with BH₃—SMe₂ to provide 54B.

Compound 54B was then elaborated into 54 (MS m/z=295, MH+) as previouslydescribed in Example 3 (Step 3).

Preparative Example 55

A Smith process vial was charged with a stir bar, compound 54B (0.33 g,1.54 mmol), CuCN (0.276 g, 3.08 mmol) and DMF (3 mL). The reactionvessel was sealed and heated to 120° C. for 3 h under microwaveirradiation. After cooling, the reaction mixture was transferred to around bottom flask and concentrated under vacuum. Compound 55A wasobtained quantitatively by continuous extraction with EtOAc in a Soxletapparatus.

Compound 55A was then elaborated into 55 (MS m/z=242, MH+) as previouslydescribed in Example 3 (Step 3).

Preparative Example 56

In a manner similar to that previously described,2-chloro-4,6-dinitrophenol was sequentially reduced with SnCl₂ (Example19, Step 2), treated with chloroacetyl chloride, reduced with BH₃—SMe₂(Example 3, Steps 1-2), protected with Boc₂O (Example 5, Step 1), andreduced again with SnCl₂ to yield compound 56A.

To a solution of compound 56A (0.29 g, 1 mmol) in anhydrous DCM (3 ml)was added 4-nitrophenylchioroformate (0.24 g, 1.2 mmol) and pyridine(0.13 ml, 1.57 mmol). After stirring overnight at RT, the reaction wasquenched with sat. NH₄Cl solution and extracted with DCM. The organicphase was then concentrated. A solution of this residue in CH₃CN (5 mL)was treated with 40% MeNH₂ in H₂O (20 mL) and heated in a sealed tube at90° C. overnight. The mixture was cooled, stirred at RT overnight, andthen quenched with water. The reaction was concentrated, diluted withwater and extracted with EtOAc. The organic phase was dried (MgSO₄),filtered, and concentrated to give 56B.

As described previously in Example 5 (Step 4) and Example 3 (Step 3),56B was deprotected and converted to 56. MS m/z=322 (MH+).

Preparative Example 57

Compound 127 (0.388 g, 1.22 mmol) was dissolved in anhydrous DCM (10 mL)and cooled to −78° C. To this solution was added 1.0M BBr₃ in DCM (6.1mL) dropwise. The reaction mixture was stirred at −78° C. for 30 min andthen at RT for 3 h. The reaction was quenched with water and neutralizedwith 2N NaOH solution. The mixture was separated and the aqueous phasewas extracted with DCM (3×10 mL). The organic phase was dried (MgSO₄),filtered, and concentrated under vacuum. The residue was purified byflash column chromatography (DCM containing 2 to 8% of 7N NH₃ in MeOH)to afford compound 57 in 30% yield. MS m/z=305 (MH+).

Preparative Example 58

In a manner similar to that described in Example 37, compound 58A(prepared in Example 6) and 58B (Bioconjugate Chemistry, 13, 333-350,2002) were reacted with HATU to provide 58C. MS m/z=572 (MH+)

Steps 2-3

A solution of 58C (720 mg, 1.3 mmol) in THF (50 mL) was treated withBH₃—SMe₂ (5 mL, 2 M in THF) and heated at 80° C. for 12 h. After it wascooled to 25° C., MeOH (15 mL) was added dropwise until bubbling ceased.The solvent was removed and partitioned between EtOAc and water. Theorganic phase was dried over Na₂SO₄ and concentrated. The crude residuewas stirred in DCM/TFA (1:3, 5 mL) at 25° C. for 4 h. Solvent wasremoved and the residue was partitioned between EtOAc and water. Theorganic phase was dried and concentrated. Column chromatography andpreparative TLC (DCM containing 5% of 7N NH₃/MeOH) gave 58. MS m/z=316(MH+).

Preparative Example 59

In a manner similar to that described in Example 3 (Step 4 then Steps1-2), methyl 2-hydroxy-3-nitrobenzoate was sequentially hydrogenated,treated with chloroacetylchloride, and reduced with BH₃—SMe₂ to yieldcompound 59A.

Step 4

Compound 59A was treated with 4-imidazolecarboxaldehyde to afford thetitle compound 59 in a manner similar to that described in Example 3(Step 3). MS m/z=274 (MH+).

Preparative Example 60

A mixture of LiBH₄ (44 mg, 2 mmol) and 59A (400 mg, 2 mmol) in THF (50mL) was stirred at RT for 4 h and then concentrated. The residue waspartitioned between EtOAc and water. The organic phase was dried andconcentrated to give 60A (300 mg, 91%).

Compound 60A was converted to 60 in a manner similar to that describedin Example 3 (Step 3). MS m/z=246 (MH+).

Preparative Example 61

To 2-chloro-5-hydroxypyridine (61A) in acetone (80 mL) was added K₂CO₃(8.96 g, 65 mmol) and methylchloroacetate (2.54 mL, 29 mmol). Themixture was heated at 60° C. for 4 h. After cooling to RT, the mixturewas filtered, and the solids were washed with acetone (50 mL). Thefiltrate was concentrated in vacuo to give 4.3 g intermediate (92%yield). The intermediate (4.3 g, 21.3 mmol) was dissolved in CHCl₃ (75mL) and treated with m-chloroperbenzoic acid (4.78 g, 27.7 mmol). Theresulting solution was heated at 50° C. for 4 h, then stirred at RTovernight. The mixture was treated with sodium sulfate, filtered andconcentrated in vacuo. Flash column chromatography (5%-10% MeOH in DCM)provided 61B (3.46 g, 75%).

The N-oxide 61 B (1.0 g, 4.61 mmol) was dissolved in H₂SO₄ (2 mL) at 0°C. HNO₃ (1 mL) was added slowly over several minutes. The reactionmixture was then placed in an oil bath heated to 40° C. The temperaturewas slowly raised to 75° C. over 1 h and then maintained there for 2 h.The mixture was then poured over ice and adjusted to pH 9 by theaddition of 50% NaOH. Water was removed in vacuo, and the resultantsolids were washed with MeOH to yield crude nitro pyridine N-oxideintermediate (2.6 g). A portion of this intermediate (1.33 g, 5.3 mmol)was dissolved in MeOH (50 mL) and treated with H₂SO₄ (1 mL). The mixturewas heated at 70° C. for 2 h and then concentrated. The residue wastreated with 1N NaOH (20 mL) and EtOAc (50 mL). The solution wasextracted with EtOAc (2×50 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to give compound61C (1.4 g, 100%).

A mixture of 61C (0.06 g, 0.23 mmol) in MeOH (2 mL) was treated withiron powder (0.09 g, 1.61 mmol) and HOAc (0.08 mL). The resultingsolution was heated at 70° C. for 4 h. The hot solution was filteredthrough a pad of celite and concentrated. The residue was taken up inMeOH (2 mL) and treated with K₂CO₃ (0.073 g, 0.53 mmol). After heatingat 65° C. for 2 h, the solvent was removed in vacuo and the productpurified by preparative TLC (5% MeOH in DCM) to give compound 61D (0.032g, 76%).

In a manner similar to that found in Example 3 (Step 2) and Example 5(Step 1), compound 61D was reduced and protected to give compound 61E.

A mixture of 61E (0.250 g, 0.91 mmol), benzophenoneimine (0.152 mL, 0.91mmol), tris(dibenzylideneacetone dipalladium(0) (0.004 g, 0.0045 mmol),rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (0.004 g, 0.007mmol), and NaOtBu (0.088 g, 0.91 mmol) in toluene (8 mL) in a culturetube was heated in a rotating oven at 80° C. overnight. After cooling toRT, the contents were transferred to a round-bottomed flask and treatedwith several scoops of silica gel. The solvent was removed in vacuo andthe product purified by flash column chromatography (10% to 50%EtOAc-hexanes) to give 61F (0.205 g, 54%).

A mixture of 61F (0.205 g, 0.5 mmol) in THF (4 mL) was treated with 15%aqueous citric acid solution (4 mL). The resulting solution was stirredat RT overnight. Saturated aqueous NaHCO₃ (5 mL) was added and thesolution was extracted with EtOAc (2×25 mL). The organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo. Theproduct was purified by flash column chromatography (10% to 50%EtOAc-hexanes) to give 61G (0.114 g, 91%).

In a manner similar to that found in Example 3 (Step 5), Example 5 (Step4) and Example 3 (Step 3), compound 61G was sequentially treated withClCO₂Me, deprotected and converted the title compound 61. MS m/z=290(MH+).

Preparative Example 62

A slurry of 38 in anhydrous DCE (4 ml) and anhydrous THF (4 ml) wastreated with anhydrous TEA (0.2 ml) followed by benzenesulfonyl chloride(0.070 mL). After 2 h at RT, additional benzenesulfonyl (0.2 mL) wasadded. The mixture was stirred for 1 h, then diluted with CH₂Cl₂, washedwith brine, dried (Na₂SO₄), and concentrated. Preparative TLCchromatography (9% MeOH/CH₂Cl₂) afforded 62 (43 mg). The followingcompounds were prepared following essentially the same procedure asdescribed above.

MS Cpd Structure (MH+) 100

230 101

230 102

230 103

216 104

234 105

248 106

341 107

327 108

349 109

317 110

329 111

301 112

287 113

273 114

288 115

262 116

293 117

217 118

217 119

289 120

289 121

241 122

289 123

309 124

312 125

259 126

291 127

319 128

303 129

275 130

303 131

306 132

277 133

327 134

320 135

321 136

320 137

290 138

245 139

303 140

275 141

275 142

354 143

289 144

318 145

300 146

274 147

437 148

323 149

229 150

311 151

317 152

276 153

306 154

337 155

323 156

287 157

301 158

301 159

331 160

361 161

436 162

355 163

331 164

345 165

375 166

419 167

405 168

327 169

341 170

332 171

314 172

321 173

321 174

291 175

263 176

335 177

277 178

335 179

349 180

349 181

332 182

286 183

256 184

314 185

328 186

327 187

376 188

333 189

329 190

299 191

357 192

371 193

371 194

385 195

370 196

384 197

354 198

339 199

353 200

338 201

352 202

322 203

392 204

406 205

406 206

389 207

289 208

333 209

343 210

327 211

350 212

380 213

368 214

351 215

390 216

369 217

356 218

384 219

355 220

303 221

365 222

289 223

316 224

274 225

304 226

303 227

288 228

304 229

324 230

318 231

348 232

336 233

337 234

351 235

352 236

350 237

331 238

330 239

316 240

317 241

304 242

317 243

318 244

332 245

330 246

347 247

328 248

390 249

349 250

381 251

351 252

381 253

275 254

277 255

309 256

345 257

331 258

331 259

407 260

361 261

247 262

341 263

373 264

345 265

359 266

335 267

351 268

365 269

365 270

391 271

317 272

331

Assay:

Efficacy agonist activity values (E_(max), GTPγS assay) for α2C weredetermined by following the general procedure detailed by Umland et. al(“Receptor reserve analysis of the human α_(2c)-adrenoceptor using[³⁵S]GTPγS and cAMP functional assays” European Journal of Pharmacology2001, 411, 211-221). For the purposes of the present invention, acompound is defined to be an active agonist of the α2C receptor subtypeif the compound's efficacy at the α2C receptor is ≧30% E_(max) (GTPγSassay). A compound is a functionally selective agonist of the α2Creceptor subtype over the α2A receptor subtype if the compound'sefficacy at the α2C receptor is ≧30% E_(max) (GTPγS assay) and itsefficacy at the α2A receptor is ≧30% E_(max) (GTPγS assay).

The following compounds were evaluated to be active or functionallyselective agonists of the α2C receptor subtype based on the previouslydefined definition: 1, 3, 3D, 3E, 5, 6, 6E, 7, 8, 9E, 9G, 91, 9K, 9L,9M, 9N, 9P, 9Q, 9R, 9S, 12, 13, 14, 14B 15, 19, 19D, 20, 21, 22, 24,24D, 25B, 26, 26A, 26B, 27E, 28, 28D, 29, 30, 37, 38, 46, 51, 53, 54,55, 57, 58, 114, 117, 124, 125, 129, 130, 132, 134, 135, 137, 139, 142,144, 145, 148, 151, 152, 158, 159, 160, 162, 163, 164, 165, 167, 168,169, 171, 178, 181, 218, 223, 231, 232, 235, 236, 238, 239, 240, 242,243, 244, 245, 246, 247, 248, 249, and 250.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A compound represented by the structural formula:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: A is a 5-membered heterocyclic ring containing 1-3 heteroatoms,and is substituted with at least one R⁵; X is —O—, —S(O)_(p)—, or—N(R⁶)—; J¹, J², J³, and J⁴ are independently —N—, —N(O)— or —C(R²)—,provided that 0-3 of J¹, J², J³ and J⁴ are —N—; R² is independentlyselected from the group consisting of H, —OH, halo, —CN, —NO₂,—(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR⁷, —(CH₂)_(q)OYR⁷, —(CH₂)_(q)ON═CR⁷R^(7′),—P(═O)(OR⁷)(OR^(7′)), —P(═O)(N R⁷R^(7′))₂, —P(═O)R⁸ ₂, and alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heterocyclyl groups optionally substituted with atleast one R⁵; Y is selected from the group consisting of a bond,—C(═O)—, —C(═O)NR⁷—, —C(═O)O—, —C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—,—C(═NR⁷)NR⁷O—, —S(O)_(P)—, —SO₂NR⁷—, and —C(S)NR⁷—; R³ is independentlyselected from the group consisting of H and (═O), and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵,provided that when n is 3 or 4, no more than 2 of the R³ groups may be(═O); R⁴ is independently selected from the group consisting of H and CNand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁵ is independently selected from the group consistingof H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents;R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁸ and —SO₂NR⁷R^(7′); R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; orR⁷ and R^(7′) together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ringhaving, in addition to the N atom, 1 or 2 additional hetero atomsselected from the group consisting of O, N, —N(R⁹)— and S, wherein saidrings are optionally substituted by 1 to 5 independently selected R⁵moieties, R⁸ is independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁹is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1-5; n is1-3; p is 0-2; q is 0-6; and w is 0-4. with the following provisos: (a)if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ is H, A is3H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not —C(═O)-naphthyl; (b)if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ is H, A is 1H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not —S(O₂)-naphthyl; and(c) if J¹, J², and J⁴ are each —C(H)—, J³ is —C(Br)—, n is 2, m is 1, R³is 3-benzyl, R⁴ is H, A is 1 H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶is not —C(O₂)benzyl.
 2. The compound of claim 1, wherein: J¹-J⁴ are each—C(R²)—; A is a 5-membered heterocyclic ring containing 1-3 heteroatoms,and is substituted with at least one R⁵; X is —O—, —S(O)_(P), or—N(R⁶)—; R² is independently selected from the group consisting of H,—OH, halo, —CN, —NO₂, —(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR^(7′),—(CH₂)_(q)OYR⁷, —(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)),—P(═O)N(R⁷R^(7′))₂, —P(═O)R⁷R^(7′), and alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheterocyclyl groups optionally substituted with at least one R⁵; Y isselected from the group consisting of a bond, —C(═O)—, —C(═O)NR⁷—,—C(═O)O—, —C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—,—S(O)_(p)—, —SO₂NR⁷—, —C(S)NR⁷—; R³ is independently selected from thegroup consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one R⁵; R⁴ is independently selected from thegroup consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one R⁵; R⁵ is independently selected from thegroup consisting of H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷substituents; R⁶ is independently selected from the group consisting ofH and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—SR⁷ substituents, and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and—SO₂NR⁷R^(7′); R⁷ is independently selected from the group consisting ofH and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;R^(7′) is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; orR⁷ and R⁷ together with the nitrogen atom together form a 3- to8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, inaddition to the N atom, 1 or 2 additional hetero atoms selected from thegroup consisting of O, N, —N(R⁹)— and S, wherein said rings areoptionally substituted by 1 to 5 independently selected R⁵ moieties, R⁸is independently selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted with at east one ofhalo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁹ isindependently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1 or 2; n is1 or 2; p is 0-2; q is 0-3; and w is 0-4.
 3. The compound of claim 2,wherein A is imidazolyl.
 4. The compound of claim 2, wherein X is —O—.5. The compound of claim 2, wherein X is —N(R⁶)—.
 6. A compoundrepresented by the structural formula:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: X is —O—, —S(O)_(p)—, or —N(R⁶)—; J¹, J², J³, and J⁴ areindependently —N— or —C(R²)—, provided that 0-3 of J¹, J², J³ and J⁴ are—N—; R² is independently selected from the group consisting of H, —OH,halo, —CN, —NO₂, —(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR^(7′), —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(O R^(7′)), —P(═O)(NR⁷R^(7′))₂,—P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclyl groupsoptionally substituted with at least one R⁵; Y is selected from thegroup consisting of a bond, —C(═O)—, —C(═O)NR⁷—, —C(═O)O—, —C(═NR⁷)—,—C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—, —S(O)_(p)—, SO₂NR⁷—, and—C(S)NR⁷—; R³ is independently selected from the group consisting of Hand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁴ is independently selected from the group consistingof H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁵ is independently selected from the group consistingof H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents;R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′); R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁷is independently selected from the group consisting of selected from thegroup consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which isoptionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; or R⁷ and R^(7′) together with thenitrogen atom to which they are attached form a 3- to 8-memberedheterocyclyl, heterocyclenyl or heteroaryl ring having, in addition tothe N atom, 1 or 2 additional hetero atoms selected from the groupconsisting of O, N, —N(R⁹)— and S, wherein said rings are optionallysubstituted by 1 to 5 independently selected R⁵ moieties, R⁸ isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted with at least one ofhalo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁹ isindependently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1-5; n is1-3; p is 0-2; q is 0-6; z is 0-3; and w is 0-4, with the followingprovisos: (a) if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ is H, A is3H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not —C(═O)-naphthyl; (b)if J¹-J⁴ are each —C(H)—, n is 1, m is 1, R⁴ is H, A is 1H-imidazol-4-yl, and X is —N(R⁶)—, then R⁶ is not —S(O₂)-naphthyl; and(c) if J¹, J², and J⁴ are each —C(H)—, J³ is —C(Br)—, n is 2, m is 1, R³is 3-benzyl, R⁴ is H, and X is —N(R⁶)—, then R⁶ is not —C(O₂)benzyl. 7.A compound represented by the structural formula:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: R¹ is selected from the group consisting of H, —OH, halo, —CN,—NO₂, —SR⁷—(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR^(7′), —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)), —P(═O)(NR⁷R^(7′))₂,—P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; X is —O—, —S(O)_(p)—, or —N(R⁶)—; Y is selected fromthe group consisting of a bond, —C(═O)—, —C(═O)NR⁷—, —C(═O)O—,—C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—, —S(O)_(p)—, SO₂NR⁷—,and —C(S)NR⁷—; R³ is independently selected from the group consisting ofH and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁴ is independently selected from the group consistingof H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁵ is independently selected from the group consistingof H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents;R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —N(R⁷)₂, and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′); R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;R^(7′) is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; orR⁷ and R^(7′) together with the nitrogen atom to which they are attachedform a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ringhaving, in addition to the N atom, 1 or 2 additional hetero atomsselected from the group consisting of O, N, —N(R⁹)— and S, wherein saidrings are optionally substituted by 1 to 5 independently selected R⁵moieties, R⁸ is independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁹is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, —CN, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1-5; n is1-3; p is 0-2; q is 0-6; z is 0-3; and w is 0-4, with the followingprovisos: (a) if n is 1, m is 1, R⁴ is H, and X is —N(R⁶)—, then R⁶ isnot —C(═O)-naphthyl; and (b) if n is 1, m is 1, R⁴ is H, and X is—N(R⁶)—, then R⁶ is not —S(O₂)-naphthyl. (c) if R¹ is Br, n is 2, m is1, R³ is 3-benzyl, R⁴ is H, A is 1H-imidazol-4-yl, and X is —N(R⁶)—,then R⁶ is not —C(O₂)benzyl.
 8. The compound of claim 7 wherein X is—O—, n is 1, m is 1, and R⁴ is H.
 9. The compound of claim 7, wherein Xis —N(R⁶)—, n is 1, m is 1, and R⁴ is H.
 10. A compound represented bythe structural formula:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: R¹ is selected from the group consisting of H, —OH, halo, —CN,—NO₂, —SR⁷—(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR⁷′, —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)), —P(═O)(NR⁷R^(7′))₂,P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; X is —O—, S(O)_(p)—, or —N(R⁶)—; J¹, J², and J⁴ areindependently —N— or —C(R²)—, provided that 0-3 of J², and J⁴ are —N—;R² is independently selected from the group consisting of H, —OH, halo,—CN, —NO₂, —(CH₂)_(p)YR⁷, —(CH₂)_(p)NR⁷YR^(7′), —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)), —P(═O)(NR⁷R^(7′))₂,—P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclyl groupsoptionally substituted with at least one R⁵; Y is selected from thegroup consisting of a bond, —C(═O)—, —C(═O)NR⁷—, —C(═O)O—, —C(═NR⁷)—,—C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—, —S(O)_(p)—, SO₂NR⁷—, and—C(S)NR⁷—; R³ is independently selected from the group consisting of Hand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁴ is independently selected from the group consistingof H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R⁵ is independently selected from the group consistingof H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —S(O)_(p)R⁷, and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷substituents; R⁶ is independently selected from the groupconsisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one of halo, —OH, —CN,—NO₂, —NR⁷R^(7′), and —SR⁷ substituents, and —C(═O)R⁷, —C(═O)OR⁷,—C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′); R⁷ is independently selectedfrom the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; R^(7′) is independently selected fromthe group consisting of selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; orR⁷ and R⁷ together with the nitrogen atom together form a 3- to8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, inaddition to the N atom, 1 or 2 additional hetero atoms selected from thegroup consisting of O, N, —N(R⁹)— and S, wherein said rings areoptionally substituted by 1 to 5 independently selected R⁵ moieties, R⁸is independently selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted with at least one ofhalo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹substituents; R⁹ isindependently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1-5; n is1-3; p is 0-2; q is 0-6; z is 0-3; and w is 0-4, with the followingprovisos: (a) if J¹, J², and J⁴ are each —C(H)—, R¹ is H, n is 1, m is1, R⁴ is H, and X is —N(R⁶)—, then R⁶ is not —C(═O)-naphthyl; (b) if J¹,J², and J⁴ are each —C(H)—, R¹ is H, n is 1, m is 1, R⁴ is H, and X is—N(R⁶)—, then R⁶ is not —S(O₂)-naphthyl; and (c) if J¹, J², and J⁴ areeach —C(H)—, R¹ is Br, n is 2, m is 1, R³ is 3-benzyl, R⁴ is H, and X is—N(R⁶)—, then R⁶ is not —C(O₂)benzyl.
 11. The compound of claim 10,wherein X is —O—, n is 1, m is 1, and R⁴ is H.
 12. The compound of claim10, wherein X is —N(R⁶)—, n is 1, m is 1, and R⁴ is H.
 13. The compoundof claim 10, wherein R¹ is selected from the group consisting of—(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR^(7′), —(CH₂)_(q)OYR⁷, and—(CH₂)_(q)ON═CR⁷R^(7′).
 14. A compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 15. Apharmaceutical composition comprising at least one compound of claim 1,or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, adjuvant or vehicle.
 16. Apharmaceutical composition comprising at least one compound of claim 14,or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, adjuvant or vehicle.
 17. Thepharmaceutical composition of claim 15, further comprising one or moreadditional therapeutic agents.
 18. The pharmaceutical composition ofclaim 16, further comprising one or more additional therapeutic agents.19. The pharmaceutical composition of claim 17, wherein said additionaltherapeutic agents are selected from the group consisting ofanti-inflammatory steroids, PDE-4 inhibitors, anti-muscarinic agents,cromolyn sodium, H₁ receptor antagonists, 5-HT₁ agonists, NSAIDs,angiotensin-converting enzyme inhibitors, angiotensin II receptoragonists, β-blockers, β-agonists, leukotriene antagonists, diuretics,aldosterone antagonists, ionotropic agents, natriuretic peptides, painmanagement agents, anti-anxiety agents, anti-migraine agents, andtherapeutic agents suitable for treating heart conditions, psychoticdisorders, and glaucoma.
 20. The pharmaceutical composition of claim 18,wherein said additional therapeutic agents are selected from the groupconsisting of steroids, PDE-4 inhibitors, anti-muscarinic agents,cromolyn sodium, H₁ receptor antagonists, 5-HT₁ agonists, NSAIDs,angiotensin-converting enzyme inhibitors, angiotensin II receptoragonists, β-blockers, β-agonists, leukotriene antagonists, diuretics,aldosterone antagonists, ionotropic agents, natriuretic peptides, painmanagement agents, anti-anxiety agents, anti-migraine agents, andtherapeutic agents suitable for treating heart conditions, psychoticdisorders, and glaucoma.
 21. A method for selectively stimulating α2Cadrenergic receptors in a cell in need thereof, comprising contactingsaid cell with a therapeutically effective amount of at least onecompound of formula I:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: A is a 5-membered heterocyclic ring containing 1-3 heteroatoms,and is substituted with at least one R⁵; X is —O—, —S(O)_(p)—, or—N(R⁶)—; J¹, J², J³, and J⁴ are independently —N—, —N(O)— or —C(R²)—,provided that 0-3 of J¹, J², J³ and J⁴ are —N—; R² is independentlyselected from the group consisting of H, —OH, halo, —CN, —NO₂,—(CH₂)_(q)YR^(7′), —(CH₂)_(q)NR⁷YR^(7′), —(CH₂)_(q)YR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)), —P(═O)(NR⁷R^(7′))₂,—P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclyl groupsoptionally substituted with at least one R⁵; Y is selected from thegroup consisting of a bond, —C(═O)—, —C(═O)NR⁷—, —C(═O)O—, —C(═NR⁷)—,—C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—, —S(O)_(p)—, —SO₂NR⁷—, and—C(S)NR⁷—; R³ is independently selected from the group consisting of Hand (═O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵, provided that when n is 3 or 4, no more than 2 of theR³ groups may be (═O); R⁴ is independently selected from the groupconsisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one R⁵; R⁵ is independently selected from thegroup consisting of H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents;R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′); R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;R^(7′) is independently selected from the group consisting of selectedfrom the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; or R⁷ and R⁷ together with thenitrogen atom to which they are attached form a 3- to 8-memberedheterocyclyl, heterocyclenyl or heteroaryl ring having, in addition tothe N atom, 1 or 2 additional hetero atoms selected from the groupconsisting of 0, N, —N(R⁹)— and S, wherein said rings are optionallysubstituted by 1 to 5 independently selected R⁵ moieties, R⁸ isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted with at least one ofhalo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R⁹ isindependently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; and R¹⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and—SR¹¹ substituents; R¹¹ is a moiety independently selected from thegroup consisting of H, —CN, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 1-5; n is1-3; p is 0-2; q is 0-6; and w is 0-4.
 22. A method for treating one ormore conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment at least onecompound of formula I:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: A is a 5-membered heterocyclic ring containing 1-3 heteroatoms,and is substituted with at least one R⁵; X is —O—, —S(O)_(p)—, or—N(R⁶)—; J¹, J², J³, and J⁴ are independently —N—, —N(O)— or —C(R²)—,provided that 0-3 of J¹, J², J³ and J⁴ are —N—; R² is independentlyselected from the group consisting of H, —OH, halo, —CN, —NO₂,—(CH₂)_(q)YR⁷, —(CH₂)_(q)NR⁷YR^(7′), —(CH₂)_(q)OYR⁷,—(CH₂)_(q)ON═CR⁷R^(7′), —P(═O)(OR⁷)(OR^(7′)), —P(═O)(NR⁷R^(7′))₂,—P(═O)R⁸ ₂, and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclyl groupsoptionally substituted with at least one R⁵; Y is selected from thegroup consisting of a bond, —C(═O)—, —C(═O)NR⁷—, C(═O)O—, —C(═NR⁷)—,—C(═NOR⁷)—, —C(═NR⁷)NR⁷—, —C(═NR⁷)NR⁷O—, —S(O)_(p)—, SO₂NR⁷—, and—C(S)NR⁷—; R³ is independently selected from the group consisting of Hand (═O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵, provided that when n is 3 or 4, no more than 2 of theR³ groups may be (═O); R⁴ is independently selected from the groupconsisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one R⁵; R⁵ is independently selected from thegroup consisting of H, halo, —OH, —CN, —NO₂, —NR⁷R^(7′), —SR⁷, andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents;R⁶ is independently selected from the group consisting of H and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —SR⁷ substituents,and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′); R⁷is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents;R^(7′) is independently selected from the group consisting of selectedfrom the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹ substituents; or R⁷ and R^(7′) together with thenitrogen atom together form a 3- to 8-membered heterocyclyl,heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1or 2 additional hetero atoms selected from the group consisting of O, N,N(R⁹)— and S, wherein said rings are optionally substituted by 1 to 5independently selected R⁵ moieties, R⁸ is independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which isoptionally substituted with at least one of halo, —OH, —CN, —NO₂,—N(R¹¹)₂, and —SR¹¹substituents; R⁹ is independently selected from thegroup consisting of H, —C(O)—R¹⁰, —C(O)—OR¹⁰, and —S(O)_(p)—OR¹⁰ andalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; andR¹⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups,each of which is optionally substituted with at least one of halo, —OH,—CN, —NO₂, —N(R¹¹)₂, and —SR¹¹ substituents; R¹¹ is a moietyindependently selected from the group consisting of H, —CN. alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2; q is 0-6; and w is 0-4.23. The method of claim 22, wherein J¹-J⁴ are each —C(R²)—, n is 1, A isimidazolyl, and X is —O—.
 24. The method of claim 22, wherein J¹-J⁴ areeach —C(H)—, n is 1, A is imidazolyl, and X is —O—.
 25. The method ofclaim 22, wherein J¹-J⁴ are each —C(R²)—, n is 1, A is imidazolyl, and Xis —N(R⁶)—.
 26. The method of claim 22, wherein J¹-J⁴ are each —C(R²)—,n is 1, A is imidazolyl, and X is —S(O)_(p)—.
 27. A method for treatingone or more conditions associated with α2C adrenergic receptors,comprising administering to a mammal in need of such treatment acompound of claim 14 or a pharmaceutically acceptable salt or solvatethereof.
 28. The method of claim 22, wherein the conditions are selectedfrom the group consisting of allergic rhinitis, congestion, pain,diarrhea, glaucoma, congestive heart failure, cardiac ischemia, manicdisorders, depression, anxiety, migraine, stress-induced urinaryincontinence, neuronal damage from ischemia and schizophrenia.
 29. Themethod of claim 22, wherein the conditions are selected from the groupconsisting of allergic rhinitis, congestion, pain, diarrhea, glaucoma,congestive heart failure, cardiac ischemia, manic disorders, depression,anxiety, and schizophrenia.
 30. The method of claim 28, wherein thecondition is congestion.
 31. The method of claim 29, wherein thecondition is congestion.
 32. The method of claim 30, wherein thecongestion is associated with perennial allergic rhinitis, seasonalallergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitismedicamentosa, sinusitis, acute rhinosinusitis, or chronicrhinosinusitis.
 33. The method of claim 30, wherein the congestion iscaused by polyps or is virally induced.
 34. The method of claim 31,wherein the congestion is associated with perennial allergic rhinitis,seasonal allergic rhinitis, non-allergic rhinitis, vasomotor rhinitis,rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronicrhinosinusitis.
 35. The method of claim 31, wherein the congestion iscaused by polyps or is virally induced.
 36. The method of claim 28,wherein the condition is pain.
 37. The method of claim 36, wherein thepain is associated with neuropathy, inflammation, arthritis or diabetes.38. The method of claim 24, wherein the condition is pain.
 39. Themethod of claim 38, wherein the pain is associated with neuropathy,inflammation, arthritis or diabetes.
 40. A compound of claim 1, inisolated and purified form.
 41. A compound of claim 1 having theformula:


42. A compound of claim 1 having the formula:


43. A compound of claim 1 having the formula:


44. A compound of claim 1 having the formula:


45. A compound of claim 1 having the formula:


46. A method for the treatment of congestion in a mammal in need thereofwhich comprises administering to a mammal an effective dose of at leastone compound having adrenergic activity wherein said compound is afunctionally selective agonist of the α2c receptor.
 47. The method ofclaim 46, wherein the functionally selective agonist of the α2c receptorhas an efficacy that is greater than or equal to 30% E_(max) whenassayed in the GTPγS assay.
 48. A method for the treatment of congestionin a mammal in need thereof without modifying the blood pressure at atherapeutic dose which comprises administering to the mammal aneffective dose of at least one compound having adrenergic activitywherein said compound is a functionally selective agonist of the α2creceptor.